Beruflich Dokumente
Kultur Dokumente
DOI 10.1007/s00415-011-6153-3
REVIEW
Received: 30 May 2011 / Accepted: 16 June 2011 / Published online: 5 July 2011
Springer-Verlag 2011
. Cervera S. Amaro A
. Chamorro (&)
A
Comprehensive Stroke Center, Hospital Clinic, Institut
dInvestigacions Biome`diques August Pi i Sunyer (IDIBAPS),
University of Barcelona, 170 Villarroel, 08036 Barcelona, Spain
e-mail: achamorro@ub.edu
123
decisions reviewed in this article are whether anticoagulation should be restarted after OAC-ICH, and when
anticoagulant treatment should be resumed. The newer
oral anticoagulants, which are increasingly being introduced for thromboembolism prevention, may confer a
lower risk of intracranial bleeding than warfarin, although
they do not have an antidote and their anticoagulant effect
is difficult to monitor.
Keywords Intracerebral hemorrhage Warfarin
Oral anticoagulation Outcome
Introduction
Warfarin is the most widely used oral anticoagulant (OAC)
in the world, although acenocoumarol, phenprocoumon or
anisindione are also frequently prescribed in several
countries. Warfarin inhibits the vitamin K-dependent posttranslational carboxylation of glutamate residues on the
N-terminal regions of coagulation factors II, VII, IX and X
by inhibiting the conversion of vitamin K 2, 3-epoxide to
reduced vitamin K [1]. The mechanism of action is comparable in the above cited OAC, being the major differences their half-lives and the duration of effect.
The benefits of OAC for thromboembolic protection are
supported by a high level of evidence in patients with
several cardiac conditions, atrial fibrillation or a history of
venous thromboembolism [2]. Nonetheless, OAC are also
notorious for having a narrow therapeutic index, numerous
drug and dietary interactions, and a significant risk of
serious bleeding that includes hemorrhagic stroke [3]. In
this review, we analyze the epidemiology, time trends,
main risk factors and pathophysiology of OAC-associated
intracerebral hemorrhage (OAC-ICH). The review also
critically discusses highly controversial therapeutic decisions that are required during the early and late phases of
this devastating condition, including the pros and cons of
different hematological approaches aimed to control the
acute bleeding, the dilemma of deciding whether oral
anticoagulation should or not be restarted, and how and
when to do it in individual cases.
Epidemiology
Approximately 1% of the population in Europe is currently
receiving OAC with vitamin K antagonists, and this proportion has increased to 1.7% in some countries [4]. About
512% of ICH is related to OAC, leading to an estimated
annual incidence in the USA of nearly 3,000 [57]. In
randomized trials, the risk of major bleeding associated
with vitamin K antagonists varied according to the clinical
condition that motivated the treatment, mechanical heart
valves (18.3%), atrial fibrillation (06.6%), coronary heart
disease (019.3%), venous thromboembolism (016.7%),
or ischemic cerebrovascular disease (213%) [8]. The most
frequent complication of OAC is gastrointestinal bleeding,
but intracranial hemorrhage (ICH) is the main cause of
fatal bleeding.
In a pooled analysis of five trials using warfarin in
patients with AF the annual rate of OAC-ICH was 0.3%
[9]. The rate of OAC-ICH is about 29 per 100,000 population/year, an incidence 7- to 10-fold higher than in the
not treated population [10]. Moreover, the incidence of
OAC-ICH is increasing and ranked only slightly behind the
incidence of subarachnoid hemorrhage in recent studies
[7]. This relentless increment can be explained by the
larger number of elderly patients that receive OAC, the
increased use of combined anticoagulant regimens or the
addition of antiplatelets, or the expanded use of OAC for
secondary stroke prevention [11]. Although the increased
number of bleeding complications is counterbalanced by a
more effective prophylaxis of thromboembolic events, the
identification of those patients at higher risk of bleeding
complications must be improved.
Pathophysiology
The primary cause of brain injury in patients with ICH or
OAC-ICH is the direct mechanical disruption of the brain
tissue [12], although secondary damage frequently occurs
as the result of mass effect, midline shift and herniation
of brain structures, particularly in subjects with large
brain hemorrhages. Several molecules have been implicated in the mechanisms of brain injury after ICH
213
123
214
123
215
Follow-up
(months)
High-risk
(%)
Medium-risk
(%)
Low-risk
(%)
48
53
12
5.4
2.0
0.9
Genetics of OAC-ICH
It has been estimated that a third of all cases of lobar ICH
are attributable to the presence of an apolipoprotein e4 or
e2 allele [51], but testing for them does not appear to
facilitate the selection of patients that can safely be treated
with warfarin [52]. Randomized clinical trials have consistently demonstrated an increased risk of bleeding among
patients in whom the target intensity of anticoagulation is
higher [3]. While a minor part of the variability in dose
requirement has been attributed to demographic and clinical factors such as age, drug interactions, concomitant
diseases, or vitamin K intake, the major contributors to the
risk of bleeding are genetic factors [53].
Genetic variants of cytochrome P450 2C9 (CYP2C9)
and vitamin K epoxide reductase (VKORC1) may influence warfarin dose and appear to modulate the risk of
bleeding, mainly at the beginning of drug intake [54, 55].
CYP2C9 encodes the enzyme cytochrome P450 2C9 that
mediates the metabolic clearance of the enantiomer
S-warfarin, which is more potent than R-warfarin, and
three different alleles termed CYP2C9*1 (wild allele),
CYP2C9*2 and CYP2C9*3 have been described. Patients
with allele variants require a lower dose of anticoagulants,
take a longer time to reach a stable dose, and are at higher
risk for over-anticoagulation and serious bleeding during
the start of treatment [54]. It has been recently suggested
that CYP2C9 genotyping could identify patients at higher
risk of bleeding [56].
VKORC1 recycles vitamin K epoxide to the reduced
form of vitamin K, an essential cofactor in the activation of
clotting factors II, VII, IX, and X [57]. VKORC1 polymorphisms account for over a 30% of the variance in the
dose of warfarin [58], and they are associated with a lower
warfarin dose during long-term therapy [55]. The increased
risk of bleeding attributable to VKORC1 is limited to the
beginning of anticoagulant therapy, while CYP2C9
sequence variants may be associated with a continued risk
of hemorrhage [59]. However, recent prospective data
show that [70% of OAC-ICH occur in patients who have
been receiving warfarin for 1 year or longer, suggesting
123
123
2000
2001
[97]
[119]
[75]
[73]
[67]
[61]
[76]
[65]
[72]
[74]
Bertram
Berwaerts
Sjoblom
Flibotte
Rosand
Flaherty
Huttner
Cucchiara
Flaherty
Zukov
88
51
21
55
190
102
42
151
42
15
79
OAC-ICH
n
No
207
267
No
891
333
142
No
No
No
No
ICH control
76
69
75
69
75
76
[18
75
71
62
67
Mean age
GCS, Hyperglycemia
ICH volume expansion
4043%
(730 days)
Warfarin use
INR [ 2.1
(90 days)
UK
Hematoma growth
Age, Male gender
(1 year)
62%
78%
(1 day1 year)
Warfarin use
3366%
52%
Hyperglycemia
(30 days)
Warfarin use,
53%
(90 days)
ICH volume
ICH volume
IV extension,
SBP
Lobar hemorrhage
Higher INR
UK
UK
Warfarin use
UK
No
INR prolongation
UK
UK
UK
Predictors of ICH
expansion volume
Predictors of
mortality or
rebleeding
5464%
43%
(4 days)
20%
4667%
(230 days)
Mortality or
poor outcome
(time of assessment)
No
Only if INR [ 3
UK
UK
UK
Yes
No
No
UK
No
Correlation of
INR with ICH ICH
expansion
GCS Glasgow Coma Scale, ICH Intracerebral hemorrhage, INR International normalized ratio, IV Intraventricular, SBP Systolic blood pressure, UK Unknown
2008
2008
2008
2006
2006
2004
2004
2000
1990
[66]
Franke
Year
Ref
Study
17
UK
56
27
UK
54
47
47
UK
Early
worsening
(%)
216
J Neurol (2012) 259:212224
217
Treatment of AOC-ICH
Reversal of anticoagulation after OAC-ICH
There is scanty evidence-based information about the proper
treatment of OAC-ICH; there are no randomized clinical
trials, current therapeutic guidelines differ in their recommendations (Table 4), and expert opinions are also variable
[79]. Nevertheless, the consensus is that anticoagulation
Bleeding definition
Preferred treatment
Indications
Australasian Society of
Thrombosis and Haemostasis
[120]
Cease warfarin
Major bleeding
IV Vitamin K ? PCC
OAC-associated ICH
IV Vitamin K ? PCC or
FFP
AHA/ASA [123]
Warfarin-associated ICH
IV Vitamin K1 510 mg
Prothrombinex (2550 IU/kg) and FFP
(150300 mL)
Life-threatening
bleeding
123
218
Table 5 Recommendations for use of specific reversal agents in OAC-ICH [78, 93]
Treatment
Dose
Special considerations
514 days
Vitamin K
224 h
Anaphylactoid reaction
15 mL/kg
Infusion 36 h
Volume overload
25100 UI/kg
Reversal 1232 h
Infusion 10 min to 1 h
Reversal 15 min
1090 lg/kg
Bolus injection
Reversal 15 min
Vitamin K
Vitamin K slowly reverts INR to its normal values, needing
224 h to be effective. All patients with OAC-ICH must be
given vitamin K. Otherwise, INR will not be corrected
completely and a rebound coagulopathy might develop
[83]. Vitamin K should be administered IV, because the
effect is too slow using the oral route. The usual doses and
infusion time are shown in Table 5.
Fresh frozen plasma
Fresh frozen plasma (FFP) has been used for many years as
the main therapy for OAC reversal, and is still the most
frequent treatment in North America. The administration of
FFP rapidly restores clotting factor levels, although rapid
correction of the INR has not been shown to improve
mortality and morbidity [84]. FFP is given IV at a dose of
15 mL/kg, although a lower dose can be used, and it
requires the concomitant administration of vitamin K. FFP
has some important disadvantages: the administration can
suffer delays due to thawing and preparation, the risk of
volume overload has to be considered in older patients, and
there is a small risk of viral transmission, passive alloimmune thrombocytopenia, anaphylactoid reactions and septicemia [85].
Prothrombin complex concentrates
Prothrombin complex concentrates (PCC) are prepared
from pooled plasma that is virally inactivated and contains
vitamin K-dependent factors. PCC is the most widely OAC
reversal agent used in Europe. There are two main types of
PCC: the three-factor concentrates contain therapeutic
amounts of factors II, IX, and X, while the four-factor
concentrates additionally contain factor VII. [86]. PCC are
given as shown in Table 5, although some authors defend
dose adjustment based on baseline INR [87]. The INR has
123
219
Author
Anticoagulation
Rebleeding
Embolism
Early
12
Early
Nagakawa [101]
Early
Early
13
Early
15
Early
34
Late
Summary of findings
83
5 (6.0%)
9 (10.8%)
Early AC
49
5 (10.2%)
6 (12.2%)
Late AC
34
3 (8.8%)
123
220
123
References
1. Whitlon DS, Sadowski JA, Suttie JW (1978) Mechanism of
coumarin action: significance of vitamin K epoxide reductase
inhibition. Biochemistry 17(8):13711377
2. Albers GW, Amarenco P, Easton JD, Sacco RL, Teal P (2008)
Antithrombotic and thrombolytic therapy for ischemic stroke:
American College of Chest Physicians evidence-based clinical
practice guidelines (8th Edition). Chest 133(6 Suppl):630S669S
3. Schulman S, Beyth RJ, Kearon C, Levine MN (2008) Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians evidence-based
clinical practice guidelines (8th Edition). Chest 133(6 Suppl):
257S298S
4. Schurgers LJ, Aebert H, Vermeer C, Bultmann B, Janzen J
(2004) Oral anticoagulant treatment: friend or foe in cardiovascular disease? Blood 104(10):32313232
5. Hart RG, Tonarelli SB, Pearce LA (2005) Avoiding central
nervous system bleeding during antithrombotic therapy: recent
data and ideas. Stroke 36(7):15881593
6. Hart RG, Boop BS, Anderson DC (1995) Oral anticoagulants
and intracranial hemorrhage. Facts and hypotheses. Stroke
26(8):14711477
7. Flaherty ML, Kissela B, Woo D, Kleindorfer D, Alwell K, Sekar
P, Moomaw CJ, Haverbusch M, Broderick JP (2007) The
increasing incidence of anticoagulant-associated intracerebral
hemorrhage. Neurology 68(2):116121
8. Levine MN, Raskob G, Beyth RJ, Kearon C, Schulman S (2004)
Hemorrhagic complications of anticoagulant treatment: the
Seventh ACCP Conference on antithrombotic and thrombolytic
therapy. Chest 126(3 Suppl):287S310S
9. (1994) Risk factors for stroke and efficacy of antithrombotic
therapy in atrial fibrillation. Analysis of pooled data from five
randomized controlled trials. Arch Intern Med 154 (13):
14491457
10. Steiner T, Rosand J, Diringer M (2006) Intracerebral hemorrhage associated with oral anticoagulant therapy: current practices and unresolved questions. Stroke 37(1):256262
11. Smith NL, Psaty BM, Furberg CD, White R, Lima JA, Newman
AB, Manolio TA (1999) Temporal trends in the use of
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
221
31. Lee KR, Betz AL, Keep RF, Chenevert TL, Kim S, Hoff JT
(1995) Intracerebral infusion of thrombin as a cause of brain
edema. J Neurosurg 83(6):10451050
32. Kitaoka T, Hua Y, Xi G, Hoff JT, Keep RF (2002) Delayed
argatroban treatment reduces edema in a rat model of intracerebral hemorrhage. Stroke 33(12):30123018
33. Brodin E, Seljeflot I, Arnesen H, Hurlen M, Appelbom H,
Hansen JB (2009) Endogenous thrombin potential (ETP) in
plasma from patients with AMI during antithrombotic treatment.
Thromb Res 123(4):573579
34. Holbrook AM, Pereira JA, Labiris R, McDonald H, Douketis
JD, Crowther M, Wells PS (2005) Systematic overview of
warfarin and its drug and food interactions. Arch Intern Med
165(10):10951106
35. Gasse C, Hollowell J, Meier CR, Haefeli WE (2005) Drug
interactions and risk of acute bleeding leading to hospitalisation
or death in patients with chronic atrial fibrillation treated with
warfarin. Thromb Haemost 94(3):537543
36. Jonsson AK, Spigset O, Jacobsson I, Hagg S (2007) Cerebral
haemorrhage induced by warfarin: the influence of drugdrug
interactions. Pharmacoepidemiol Drug Saf 16(3):309315
37. Hirsh J, Fuster V, Ansell J, Halperin JL (2003) American Heart
Association/American College of Cardiology Foundation guide
to warfarin therapy. Circulation 107(12):16921711
38. Battistella M, Mamdami MM, Juurlink DN, Rabeneck L, Laupacis A (2005) Risk of upper gastrointestinal hemorrhage in
warfarin users treated with nonselective NSAIDs or COX-2
inhibitors. Arch Intern Med 165(2):189192
39. Lee GH, Kwon SU, Kang DW (2008) Warfarin-induced intracerebral hemorrhage associated with microbleeds. J Clin Neurol
(Seoul, Korea) 4(3):131133
40. The Stroke Prevention in Reversible Ischemia Trial (SPIRIT)
Study Group (1997) A randomized trial of anticoagulants versus
aspirin after cerebral ischemia of presumed arterial origin. Ann
Neurol 42(6):857865
41. Smith EE, Rosand J, Knudsen KA, Hylek EM, Greenberg SM
(2002) Leukoaraiosis is associated with warfarin-related hemorrhage following ischemic stroke. Neurology 59(2):193197
42. Tanaka A, Ueno Y, Nakayama Y, Takano K, Takebayashi S
(1999) Small chronic hemorrhages and ischemic lesions in
association with spontaneous intracerebral hematomas. Stroke
30(8):16371642
43. Fazekas F, Kleinert R, Roob G, Kleinert G, Kapeller P, Schmidt
R, Hartung HP (1999) Histopathologic analysis of foci of signal
loss on gradient-echo T2*-weighted MR images in patients with
spontaneous intracerebral hemorrhage: evidence of microangiopathy-related microbleeds. AJNR 20(4):637642
44. Fan YH, Zhang L, Lam WW, Mok VC, Wong KS (2003)
Cerebral microbleeds as a risk factor for subsequent intracerebral hemorrhages among patients with acute ischemic stroke.
Stroke 34(10):24592462
45. Naka H, Nomura E, Takahashi T, Wakabayashi S, Mimori Y,
Kajikawa H, Kohriyama T, Matsumoto M (2006) Combinations
of the presence or absence of cerebral microbleeds and advanced
white matter hyperintensity as predictors of subsequent stroke
types. AJNR 27(4):830835
46. Lee SH, Ryu WS, Roh JK (2009) Cerebral microbleeds are a
risk factor for warfarin-related intracerebral hemorrhage. Neurology 72(2):171176
47. Beyth RJ, Quinn LM, Landefeld CS (1998) Prospective evaluation of an index for predicting the risk of major bleeding in
outpatients treated with warfarin. Am J Med 105(2):9199
48. Kuijer PM, Hutten BA, Prins MH, Buller HR (1999) Prediction
of the risk of bleeding during anticoagulant treatment for venous
thromboembolism. Arch Intern Med 159(5):457460
123
222
49. Shireman TI, Mahnken JD, Howard PA, Kresowik TF, Hou Q,
Ellerbeck EF (2006) Development of a contemporary bleeding
risk model for elderly warfarin recipients. Chest
130(5):13901396
50. Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst
S, Van Gelder IC, Al-Attar N, Hindricks G, Prendergast B,
Heidbuchel H, Alfieri O, Angelini A, Atar D, Colonna P, De
Caterina R, De Sutter J, Goette A, Gorenek B, Heldal M, Hohloser SH, Kolh P, Le Heuzey JY, Ponikowski P, Rutten FH
(2010) Guidelines for the management of atrial fibrillation: the
task force for the management of atrial fibrillation of the
European Society of Cardiology (ESC). Eur Heart J
31(19):23692429
51. Woo D, Sauerbeck LR, Kissela BM, Khoury JC, Szaflarski JP,
Gebel J, Shukla R, Pancioli AM, Jauch EC, Menon AG, Deka R,
Carrozzella JA, Moomaw CJ, Fontaine RN, Broderick JP (2002)
Genetic and environmental risk factors for intracerebral hemorrhage: preliminary results of a population-based study. Stroke
33(5):11901195
52. Eckman MH, Wong LK, Soo YO, Lam W, Yang SR, Greenberg
SM, Rosand J (2008) Patient-specific decision-making for
warfarin therapy in nonvalvular atrial fibrillation: how will
screening with genetics and imaging help? Stroke
39(12):33083315
53. Loebstein R, Yonath H, Peleg D, Almog S, Rotenberg M, Lubetsky A, Roitelman J, Harats D, Halkin H, Ezra D (2001)
Interindividual variability in sensitivity to warfarinNature or
nurture? Clin Pharmacol Ther 70(2):159164
54. Aithal GP, Day CP, Kesteven PJ, Daly AK (1999) Association
of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications.
Lancet 353(9154):717719
55. Rieder MJ, Reiner AP, Gage BF, Nickerson DA, Eby CS,
McLeod HL, Blough DK, Thummel KE, Veenstra DL, Rettie
AE (2005) Effect of VKORC1 haplotypes on transcriptional
regulation and warfarin dose. N Engl J Med 352(22):22852293
56. Klein TE, Altman RB, Eriksson N, Gage BF, Kimmel SE, Lee
MT, Limdi NA, Page D, Roden DM, Wagner MJ, Caldwell MD,
Johnson JA (2009) Estimation of the warfarin dose with clinical
and pharmacogenetic data. N Engl J Med 360(8):753764
57. Li T, Chang CY, Jin DY, Lin PJ, Khvorova A, Stafford DW
(2004) Identification of the gene for vitamin K epoxide reductase. Nature 427(6974):541544
58. Wadelius M, Chen LY, Downes K, Ghori J, Hunt S, Eriksson N,
Wallerman O, Melhus H, Wadelius C, Bentley D, Deloukas P
(2005) Common VKORC1 and GGCX polymorphisms associated with warfarin dose. Pharmacogenomics J 5(4):262270
59. Schwarz UI, Ritchie MD, Bradford Y, Li C, Dudek SM, FryeAnderson A, Kim RB, Roden DM, Stein CM (2008) Genetic
determinants of response to warfarin during initial anticoagulation. N Engl J Med 358(10):9991008
60. Genes for Cerebral Hemorrhage on Anticoagulation (GOCHA)
Collaborative Group (2009) Exploiting common genetic variation to make anticoagulation safer. Stroke 40(3 Suppl):S64S66
61. Flaherty ML, Haverbusch M, Sekar P, Kissela B, Kleindorfer D,
Moomaw CJ, Sauerbeck L, Schneider A, Broderick JP, Woo D
(2006) Long-term mortality after intracerebral hemorrhage.
Neurology 66(8):11821186
62. Foulkes MA, Wolf PA, Price TR, Mohr JP, Hier DB (1988) The
Stroke Data Bank: design, methods, and baseline characteristics.
Stroke 19(5):547554
63. Andersen KK, Olsen TS, Dehlendorff C, Kammersgaard LP
(2009) Hemorrhagic and ischemic strokes compared: stroke
severity, mortality, and risk factors. Stroke 40(6):20682072
64. Leira R, Davalos A, Silva Y, Gil-Peralta A, Tejada J, Garcia M,
Castillo J (2004) Early neurologic deterioration in intracerebral
123
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
223
99. Butler AC, Tait RC (1998) Management of oral anticoagulantinduced intracranial haemorrhage. Blood Rev 12(1):3544
100. Leker RR, Abramsky O (1998) Early anticoagulation in patients
with prosthetic heart valves and intracerebral hematoma. Neurology 50(5):14891491
101. Nakagawa T, Kubota T, Handa Y, Kawano H, Sato K (1995)
Intracranial hemorrhage due to long-term anticoagulant therapy
in patients with prosthetic heart valvesfour case reports. Neurol
Med Chir 35(3):156159
102. Tinker JH, Tarhan S (1978) Discontinuing anticoagulant therapy
in surgical patients with cardiac valve prostheses. Observations
in 180 operations. JAMA 239(8):738739
103. Chamorro A, Busse O, Obach V, Toni D, Sandercock P,
Reverter JC, Cervera A, Torres F, Davalos A (2005) The rapid
anticoagulation prevents ischemic damage study in acute
strokefinal results from the writing committee. Cerebrovasc
Dis 19(6):402404. doi:10.1159/000086100
104. Pessin MS, Estol CJ, Lafranchise F, Caplan LR (1993) Safety of
anticoagulation after hemorrhagic infarction. Neurology
43(7):12981303
105. Chamorro A, Vila N, Saiz A, Alday M, Tolosa E (1995) Early
anticoagulation after large cerebral embolic infarction: a safety
study. Neurology 45(5):861865
106. Einhaupl KM, Villringer A, Meister W, Mehraein S, Garner C,
Pellkofer M, Haberl RL, Pfister HW, Schmiedek P (1991)
Heparin treatment in sinus venous thrombosis. Lancet
338(8767):597600
107. Stam J, De Bruijn SF, DeVeber G (2002) Anticoagulation for
cerebral sinus thrombosis. Cochrane database of systematic
reviews (Online) 4:CD002005
108. Chamorro A (2001) Immediate anticoagulation in acute focal
brain ischemia revisited: gathering the evidence. Stroke
32(2):577578
109. Knudsen KA, Rosand J, Karluk D, Greenberg SM (2001)
Clinical diagnosis of cerebral amyloid angiopathy: validation of
the Boston criteria. Neurology 56(4):537539
110. PROGRESS Collaborative Group (2001) Randomised trial of a
perindopril-based blood-pressure-lowering regimen among
6,105 individuals with previous stroke or transient ischaemic
attack. Lancet 358(9287):10331041
111. ODonnell HC, Rosand J, Knudsen KA, Furie KL, Segal AZ,
Chiu RI, Ikeda D, Greenberg SM (2000) Apolipoprotein E
genotype and the risk of recurrent lobar intracerebral hemorrhage. N Engl J Med 342(4):240245
112. Eckman MH, Rosand J, Knudsen KA, Singer DE, Greenberg
SM (2003) Can patients be anticoagulated after intracerebral
hemorrhage? A decision analysis. Stroke 34(7):17101716
113. Stangier J (2008) Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate.
Clin Pharmacokinet 47(5):285295
114. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J,
Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S,
Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener
HC, Joyner CD, Wallentin L (2009) Dabigatran versus warfarin in
patients with atrial fibrillation. N Engl J Med 361(12):11391151
115. Gage BF (2009) Can we rely on RE-LY? N Engl J Med
361(12):12001202
116. van Ryn J, Stangier J, Haertter S, Liesenfeld KH, Wienen W,
Feuring M, Clemens A (2010) Dabigatran etexilatea novel,
reversible, oral direct thrombin inhibitor: interpretation of
coagulation assays and reversal of anticoagulant activity.
Thromb Haemost 103(6):11161127
117. Hylek EM (2010) Therapeutic potential of oral factor Xa
inhibitors. N Engl J Med 363(26):25592561
118. Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, Flaker G, Avezum A, Hohnloser SH, Diaz R, Talajic M,
123
224
119.
120.
121.
122.
123