Warfarin-associated intracerebral hemorrhage: Volume, anticoagulation intensity and location

doi:10.1016/j.jns.2013.06.020

Journal of the Neurological Sciences

Volume 332, Issues 1–2, 15 September 2013, Pages 75-79

https://doi.org/10.1016/j.jns.2013.06.020 Get rights and content

Abstract

Background

Warfarin use increases mortality in patients with intracerebral hemorrhage (ICH). Larger hematoma volume and infratentorial location are both major determinants of poor outcome in ICH. Although warfarin-associated intracerebral hemorrhages have greater volumes, there is uncertainty about the effects of location. We aimed to investigate the influence of warfarin on hematoma volume and location.

Methods

We conducted a retrospective study of all patients hospitalized for ICH at a large stroke center from October 2007 to January 2012. Initial CT scans were used to quantify hematoma volumes using the computer-assisted planimetric analysis. Univariate and multivariable analyses determined the influence of warfarin on hemorrhage location. Median regression analysis was performed to estimate the effects of INR on hematoma volumes.

Results

We included 404 consecutive patients with ICH of whom 69 were on warfarin. Patients on warfarin had larger hematoma volumes (median 23.9 mL vs. 14.2 mL; P = 0.046). In patients excessively anticoagulated with warfarin (defined as INR > 3.0), compared with those in the therapeutic range, brainstem ICH was more frequent (24.0% vs. 6.1%; P = 0.005). Patients with INR > 3.0 had increased odds of infratentorial hemorrhage (OR 3.63; 95% CI 1.52–8.64; P = 0.004) when compared to non-warfarin ICH patients. After adjustment for hematoma location, there was no significant association between INR and hematoma volume.

Conclusions

Patients with warfarin-associated ICH have a predilection for brainstem ICH. After adjustment for ICH location, no relationship between admission INR and hematoma volume was found.

Introduction

Warfarin-associated ICH is a major clinical problem, more common than subarachnoid hemorrhage in the United States [1]. The use of warfarin to prevent atrial fibrillation-related stroke is increasing with aging populations and better recognition [2], [3], [4]. Oral anticoagulant therapy (OAT) not only increases the risk of intracerebral hemorrhage (ICH) [5], but also worsens the severity of ICH in a dose-dependent manner [6]. The underlying mechanism by which warfarin worsens ICH prognosis has not been well established.

Larger baseline hematoma volume and infratentorial location are two major determinants of poor outcome in spontaneous ICH [7], [8]. Given that the risk of ICH increases significantly with increasing international normalized ratio (INR) in patients taking warfarin [9], it is possible that intense anticoagulation may affect the size of ICH. However, previous studies have reported conflicting results on the effect of warfarin on hematoma volume [10], [11], [12], [13]. In addition, the correlation of anticoagulant therapy and hematoma location is controversial [14], [15], [16], [17]. Some studies have suggested a higher proportion of lobar and thalamic location [10], [17], but others reported a higher rate of cerebellar hemorrhage [14], [15], [16]. It follows that the relationship of OAT with hematoma volume and location remains unresolved.

The aim of the present study was to investigate in ICH patients whether higher INR values are associated with larger baseline hematoma volumes, and to determine the relationship between warfarin therapy and hematoma location.

Section snippets

Study population

The study protocol was approved by the human research ethics committee of the Royal Melbourne Hospital. We identified all subjects aged ≥ 18 years who were hospitalized with ICH between October 1, 2007 and January 31, 2012 at this hospital. All potential cases were extracted from our prospective stroke database. Exclusion criteria were traumatic ICH, hemorrhagic transformation of cerebral infarction, ICH secondary to vascular malformation, aneurysm, vasculitis of the central nervous system, and

Results

There were 553 ICH patients treated at our hospital from October 1, 2007 to January 31, 2012. Of these, 28 were excluded due to secondary ICH, 12 due to primary IVH, 68 due to unavailable baseline CT scans or CT films unfit for computerized image analysis, and 47 due to missing initial INR values, leaving a study population of 404. Baseline characteristics of the study patients are described in Table 1.

The median age of the cohort was 74 years (interquartile range [IQR] 63 to 81), 58.9% of

Discussion

Patients with warfarin-related ICH have worse outcomes, chiefly attributed to larger hematoma volumes. In this study, we have also found a relationship between warfarin-associated ICH and infratentorial location, which may contribute to the worse prognosis in this group.

ICH is the most feared and lethal complication of warfarin therapy. It accounts for approximately 90% of the deaths from warfarin-associated intra- and extracranial hemorrhages and the majority of major functional disability

Conclusions

The results from the present study confirmed that warfarin caused larger volume hemorrhages and in addition, showed a disproportionate number of hemorrhages with infratentorial location. This may be another important determinant of the worse outcome in this population.

Sources of funding

This work was supported by the NHMRC Centre for Research Excellence Grant (1001216).

Conflict of interest statement

None.

References (30)

R. Itabashi et al.
Location of acute brain hemorrhage in patients undergoing antithrombotic therapy
J Neurol Sci
(2009)
M.C. Fang et al.
Death and disability from warfarin-associated intracranial and extracranial hemorrhages
Am J Med
(2007)
D. Poli et al.
Bleeding risk during oral anticoagulation in atrial fibrillation patients older than 80 years
J Am Coll Cardiol
(2009)
R.L. Jeffree et al.
Warfarin related intracranial haemorrhage: a case-controlled study of anticoagulation monitoring prior to spontaneous subdural or intracerebral haemorrhage
J Clin Neurosci
(2009)
R.G. Hart et al.
Avoiding central nervous system bleeding during antithrombotic therapy: recent data and ideas
Stroke
(2005)
M.C. Fang et al.
National trends in antiarrhythmic and antithrombotic medication use in atrial fibrillation
Arch Intern Med
(2004)
K. Lakshminarayan et al.
Atrial fibrillation and stroke in the general medicare population: a 10-year perspective (1992 to 2002)
Stroke
(2006)
J. Huhtakangas et al.
Effect of increased warfarin use on warfarin-related cerebral hemorrhage: a longitudinal population-based study
Stroke
(2011)
M.L. Flaherty et al.
The increasing incidence of anticoagulant-associated intracerebral hemorrhage
Neurology
(2007)
J. Rosand et al.
The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage
Arch Intern Med
(2004)

J.P. Broderick et al.

Volume of intracerebral hemorrhage. A powerful and easy-to-use predictor of 30-day mortality

Stroke

(1993)

O.G. Nilsson et al.

Prediction of death in patients with primary intracerebral hemorrhage: a prospective study of a defined population

J Neurosurg

(2002)

E.M. Hylek et al.

Risk factors for intracranial hemorrhage in outpatients taking warfarin

Ann Intern Med

(1994)

J.A. Radberg et al.

Prognostic parameters in spontaneous intracerebral hematomas with special reference to anticoagulant treatment

Stroke

(1991)

J. Berwaerts et al.

Prediction of functional outcome and in-hospital mortality after admission with oral anticoagulant-related intracerebral hemorrhage

Stroke

(2000)

Cited by (22)

Antithrombotic Treatment Prior to Intracerebral Hemorrhage: Analysis in the National Acute Stroke Israeli Registry
2018, Journal of Stroke and Cerebrovascular Diseases
Citation Excerpt :
Horstmann et al. (2013) suggested intraventricular extension as the cause for worse prognosis in anticoagulant therapy, and Flibotte et al. (2004) attributed AA-ICH's worse prognosis occurs due to increased hematoma expansion on OACs. Yet, some other studies suggest higher ICH volume on prior anticoagulant therapy.14,15,28,29 These studies attribute AA-ICH's worse prognosis to higher initial volumes, along with AA-ICH's higher incidence of hematoma expansion and intraventricular extension.
Intracerebral hemorrhage (ICH) is the most disastrous stroke subtype. Prognosis is considered worse with prior antithrombotic treatment. Our aim was to evaluate the association of prior antithrombotic treatment on the radiological and clinical outcome after ICH in a subgroup of patients included in a national registry.
Based on the National Acute Stroke Israeli (NASIS) registry during 2004, 2007, 2010, and 2013 (2-month periods), characteristics, volumetric parameters, and prognosis of a subgroup of patients with ICH were analyzed.
Among the 634 patients with ICH in the NASIS registry, 310 (49%) were not treated previously with antithrombotic medications, 232 (37%) were treated with an antiplatelet agent, and 92 (14.5%) patients were on oral anticoagulant therapy, of them 30 patients (33%) with an international normalised ratio (INR) value below 2, 33 (36%) patients with an INR value of 2-3, and 29 patients (31%) with an INR value above 3 upon admission. Patients with deep hemorrhage on prior anticoagulants treatment had the highest probability for poor outcome at hospital discharge. Patients with low bleeding volume (0-30 cm³), were likely to have admission National Institute of Health Stroke Scale < 10 (62%), while those with higher volumes (30-59 cm³ and > 60 cm³), had only 16.7% and 14.3% chance, respectively. We did not observe a significant difference between prior antithrombotic treatment and functional outcome at discharge, yet prior anticoagulant treatment was associated with higher long-term mortality rates.
Our findings, based on a national registry, support the high mortality and poor outcome of anticoagulant related ICH.
Prognostic factors and analysis of mortality due to brain haemorrhages associated with vitamin K antagonist oral anticoagulants. Results from the TAC registry
2018, Neurologia
La hemorragia intracraneal (HIC) en pacientes tratados con anticoagulantes orales antagonistas de la vitamina K (AVK) es una complicación grave y frecuentemente letal; en este trabajo estudiamos las características clínicas y los factores que se relacionan con la mortalidad en este grupo de pacientes.
Realizamos un estudio observacional, multicéntrico y retrospectivo, de ámbito nacional, basado en registros prospectivos de pacientes con ictus. Se incluyó a los pacientes ingresados en servicios de Neurología durante un período de un año y que cumplieran los criterios de inclusión: pacientes mayores de 18 años con HIC que estuvieran en tratamiento con AVK y que ingresaron durante el periodo de estudio. Se analizaron las variables clínicas y radiológicas y su evolución a 3 meses.
Incluimos a 235 pacientes provenientes de 21 hospitales. La mortalidad a los 90 días fue del 42,6%. En el modelo bivariante los factores asociados con defunción fueron: mediana en la puntuación de la escala NIHSS al ingreso (5 [RIQ = 9] vs. 17 [RIQ = 14] puntos, p < 0,01) y la presencia de una hemorragia hemisférica extensa (4,9% vs. 35%, p < 0,01; X²). Las hemorragias hemisféricas extensas, además de ser las más letales, también presentaron el tiempo más corto hasta el fallecimiento (media 16,5 días; IC del 95%, 7,1-26). Realizamos un modelo de regresión logística que evidenció que solo la NIHSS basal predijo de forma independiente el fallecimiento (odds ratio = 1,13 [IC del 95%, 1,08-1,17] por cada punto en la escala).
La HIC en pacientes tratados con AVK conlleva una elevada mortalidad asociada principal e independientemente con la situación clínica al inicio del ictus.
Intracranial haemorrhages (ICH) represent a severe and frequently lethal complication in patients treated with vitamin K antagonists (VKA). The purpose of our study is to describe the factors and clinical features associated with mortality in these patients.
We conducted an observational, retrospective, multi-centre study based on prospective stroke registries in Spain. We included all patients admitted to neurology departments during a one-year period who met the following inclusion criteria: being 18 or older, having a diagnosis of ICH, and receiving VKA. Clinical and radiological parameters and 3-month outcomes were analysed.
A total of 235 patients from 21 hospitals were included. Mortality rate at 90 days was 42.6%. Bivariate analysis showed a significant association between death and the following factors: median NIHSS score at admission (5 [IQR = 9] vs 17 [IQR = 14] points, P<.01) and presence of an extensive hemispheric haemorrhage (4.9% vs 35%, P < .01; χ²). Extensive hemispheric haemorrhages, in addition to being the most lethal type, were associated with a shorter time to death (mean of 16.5 days; 95% CI: 7.1-26). A logistic regression model showed that only baseline NIHSS scores independently predicted death (odds ratio = 1.13 [95% CI: 1.08-1.17] for each point in the scale).
ICH in patients treated with VKA is associated with high mortality rates; mortality in these patients is mainly and independently associated with the clinical situation at stroke onset.
Anticoagulation after intracerebral haemorrhage
2018, Medicina Clinica
La fibrilación auricular es responsable del 50% de los ictus de origen cardioembólico y del 20% de todos los ictus. Los ictus producidos por fibrilación auricular son más graves, discapacitantes y mortales. Los anticoa-gulantes orales tipo antivitamina K son capaces de prevenir un 64% la incidencia de ictus, a costa de incrementar el riesgo de una hemorragia intracraneal. Los anticoagulantes de acción directa tienen un 50% menos de riesgo de producir una hemorragia intracraneal que los antivitamina K. El número de pacientes anticoagulados ha aumentado considerablemente en la última década y, por consiguiente, también el de hemorragia intracraneal por anticoagulantes. Aunque su morbimortalidad es muy elevada, en los pacientes que sobreviven y están en riesgo de ictus se debe plantear si reiniciar o no la anticoagulación. Los datos existentes hasta la fecha provienen de estudios observacionales, y con ellos las guías clínicas han establecido unas recomendaciones generales con bajos niveles de evidencia, en los que recomiendan evitar la anti-coagulación en hemorragias intracraneales lobares e individualizarlo en hemorragias intracraneales profundas. A la espera de nueva evidencia científica sobre cuál puede ser la mejor estrategia preventiva, se debe individualizar la decisión en cada paciente en función de ciertos factores como son la edad, la locali-zación y etiología de la hemorragia intracraneal, qué anticoagulante produjo la hemorragia intracraneal, antecedentes de embolias previas o la presencia o no de microhemorragias cerebrales múltiples. Las opciones terapéuticas pasarían preferentemente por la utilización de los anticoagulantes de acción directa o por el cierre percutáneo de la orejuela izquierda.
Atrial fibrillation causes 50% of cardioembolic strokes and 20% of all strokes. Strokes produced by atrial fibrillation are larger, more disabling and more often fatal. Antivitamin K antagonists are able to prevent 64% of strokes, but increase the risk of intracranial haemorrhage. Direct oral anticoagulants have a 50% lower risk of producing intracranial haemorrhage than vitamin K antagonists. The number of patients receiving anticoagulation has increased markedly in the last decade and, consequently, so has the risk of anticoagulant-associated intracranial haemorrhage. Although the associated morbidity and mortality are very high, the need to resume anticoagulation must be considered among survivors at risk of stroke. Currently available data are drawn from observational studies. Based on these studies, the clinical practice guidelines have established general recommendations with low levels of evidence, which include avoiding anticoagulation in lobar intracranial haemorrhages and individualisation of anticoagulation in deep intracranial haemorrhages. Until new scientific evidence is available on the most effective preventive strategy, decisions should be individualised in each patient depending on certain factors such as age, the localisation and cause of the intracranial haemorrhage, the anticoagulant that produced the cerebral bleed, prior embolisms, and the presence or absence of multiple cerebral microhemorrhages. The treatments of choice are direct oral anticoagulants or percutaneous closure of the left atrial appendage.
Does warfarin-related intracerebral haemorrhage lead to higher costs of management?
2014, Clinical Neurology and Neurosurgery
Citation Excerpt :
The use of oral anticoagulant therapy (OAT) for stroke prevention (most commonly in patients with atrial fibrillation) increases both the risk for ICH and its severity [10,11]. Other known major predictors of poor outcome in ICH include haematoma volume, intraventricular extension and infratentorial location [9,12–18]. Approximately 5–12% of ICH is related to warfarin therapy [11,15,19].
Warfarin-related intracerebral haemorrhage is associated with significant morbidity but long term treatment costs are unknown. Our study aimed to assess the cost of warfarin-related intracerebral haemorrhage.
We included all patients with intracerebral haemorrhage between July 2006 and December 2011 at a single centre. We collected data on anticoagulant use, baseline clinical variables, discharge destinations, modified Rankin Scale at discharge and in-hospital costings. First year costings were extracted from previous studies. Multiple linear regression for treatment cost was performed with stratified analysis to assess for effect modification.
There were 694 intracerebral haemorrhage patients, with 108 (15.6%) previously on warfarin. Mean age (SD) of participants was 70.3 (13.6) and 58.5% were male. Patients on warfarin compared to those not on warfarin had significantly lower rates of discharge home (12.0% versus 18.9%, p = 0.013). Overall total costs between groups were similar, $AUD 25,767 for warfarin-related intracerebral haemorrhage and $AUD 27,388 for non-warfarin intracerebral haemorrhage (p = 0.353). Stratified analysis showed survivors of warfarin-related intracerebral haemorrhage had higher costs compared to those without warfarin ($AUD 33,419 versus $AUD 30,193, p < 0.001) as well as increased length of stay (12 days versus 8 days, p < 0.001). Inpatient mortality of patients on warfarin was associated with a shorter length of stay (p = 0.001) and lower costs.
Survival of initial haemorrhage on warfarin was associated with increased treatment cost and length of stay but this was discounted by higher rates and earlier nature of mortality in warfarinised patients.
Critical care management of intracerebral hemorrhage
2014, Critical Care Clinics
Citation Excerpt :
Warfarin use was associated with approximately 6.6% of ICH cases in the United States from 2005 to 2008, and this association is expected to increase as the population ages and more patients are placed on anticoagulants for a variety of cardiovascular indications.3 Supratherapeutic warfarin use as measured by high International Normalized Ratio (INR) correlates with case rate and poor outcome.8,9,14–16 Newer oral anticoagulants with lower potential for unpredictable therapeutic levels may confer less risk than warfarin.17
Does a location predilection exist for warfarin associated intracerebral hemorrhage?
2014, Journal of the Neurological Sciences

View all citing articles on Scopus

View full text

Warfarin-associated intracerebral hemorrhage: Volume, anticoagulation intensity and location

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Study population

Results

Discussion

Conclusions

Sources of funding

Conflict of interest statement

J Neurol Sci

Am J Med

J Am Coll Cardiol

J Clin Neurosci

Avoiding central nervous system bleeding during antithrombotic therapy: recent data and ideas

Stroke

National trends in antiarrhythmic and antithrombotic medication use in atrial fibrillation

Arch Intern Med

Atrial fibrillation and stroke in the general medicare population: a 10-year perspective (1992 to 2002)

Stroke

Effect of increased warfarin use on warfarin-related cerebral hemorrhage: a longitudinal population-based study

Stroke

The increasing incidence of anticoagulant-associated intracerebral hemorrhage

Neurology

The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage

Arch Intern Med

Volume of intracerebral hemorrhage. A powerful and easy-to-use predictor of 30-day mortality

Stroke

Prediction of death in patients with primary intracerebral hemorrhage: a prospective study of a defined population

J Neurosurg

Risk factors for intracranial hemorrhage in outpatients taking warfarin

Ann Intern Med

Prognostic parameters in spontaneous intracerebral hematomas with special reference to anticoagulant treatment

Stroke

Prediction of functional outcome and in-hospital mortality after admission with oral anticoagulant-related intracerebral hemorrhage

Stroke