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The American Journal of Medicine (2005) 118, 612– 617
CLINICAL RESEARCH STUDY
Incidence of intracranial hemorrhage in patients with
atrial fibrillation who are prone to fall
Brian F. Gage, MD, MSc,a Elena Birman–Deych, MS,a Roger Kerzner, MD,b
Martha J. Radford, MD,c David S. Nilasena, MD, MSPH, MS,d Michael W. Rich, MDb
aDivision of General Medical Sciences, Washington University School of Medicine, andbDivision of Cardiology, Washington University School of Medicine, St. Louis, Missouri;cCenter for Outcomes Research and Evaluation at Yale New Haven Health System, and Division of Cardiology, YaleSchool of Medicine, New Haven, Connecticut; and thedCenters for Medicare and Medicaid Services, Dallas, Texas.
Patients at high risk for falls are presumed to be at increased risk for intracranial
hemorrhage, and high risk for falls is cited as a contraindication to antithrombotic therapy. Data
substantiating this concern are lacking.
Quality improvement organizations identified 1245 Medicare beneficiaries who were
documented in the medical record to be at high risk of falls and 18 261 other patients with atrial
fibrillation. The patients were elderly (mean 80 years), and 48% were prescribed warfarin at hospital
discharge. The primary endpoint was subsequent hospitalization for an intracranial hemorrhage, basedon ICD-9 codes.
Rates (95% confidence interval [CI]) of intracranial hemorrhage per 100 patient-years
were 2.8 (1.9 – 4.1) in patients at high risk for falls and 1.1 (1.0 –1.3) in other patients. Rates (95% CI)of traumatic intracranial hemorrhage were 2.0 (1.3–3.1) in patients at high risk for falls and 0.34(0.27– 0.45) in other patients. Hazard ratios (95% CI) of other independent risk factors for intracranialhemorrhage were 1.4 (1.0 –3.1) for neuropsychiatric disease, 2.1 (1.6 –2.7) for prior stroke, and 1.9(1.4 –2.4) for prior major bleeding. Warfarin prescription was associated with intracranial hemorrhagemortality but not with intracranial hemorrhage occurrence. Ischemic stroke rates per 100 patient-yearswere 13.7 in patients at high risk for falls and 6.9 in other patients. Warfarin prescription in patientsprone to fall who had atrial fibrillation and multiple additional stroke risk factors appeared to protectagainst a composite endpoint of stroke, intracranial hemorrhage, myocardial infarction, and death.
Patients at high risk for falls with atrial fibrillation are at substantially increased risk
of intracranial hemorrhage, especially traumatic intracranial hemorrhage. However, because of theirhigh stroke rate, they appear to benefit from anticoagulant therapy if they have multiple stroke riskfactors.
2005 Elsevier Inc. All rights reserved.
0002-9343/$ -see front matter 2005 Elsevier Inc. All rights reserved.
Risk of Intracranial Hemorrhage in Patients Prone to Fall
In atrial fibrillation trials of carefully selected partici-
a random sample stratified by state from all Medicare ben-
pants, antithrombotic therapy prevented strokes with an
eficiaries who were hospitalized with an International Clas-
acceptable rate of intracranial hemorrhages: 0.3 intracranial
sification of Diseases, 9th Revision, Clinical Modification
hemorrhage per 100 patient-years with aspirin and 0.4 – 0.5
(ICD-9) code for atrial fibrillation (427.31) in any diagnos-
intracranial hemorrhage per 100 patient-years with warfa-
tic position and who were discharged between April 1, 1998
However, elderly patients at high risk for falls were
and March 31, 1999. We obtained inpatient (part A) and
excluded from clinical and no longitudinal data
outpatient (part B) Medicare records from 1995 through
quantify the risk of intracranial hemorrhage and stroke in
The structured abstraction of data from medical charts
Perception of traumatic intracranial hemorrhage risk in-
was performed by the Clinical Data Abstraction Centers,
fluences selection of antithrombotic therapy.
which confirmed the presence of atrial fibrillation during the
and medical record demonstrate that physicians
index admission. The remaining records were systemati-
avoid antithrombotic therapy in elderly patients with atrial
cally reviewed for risk of falls, stroke risk factors, and
fibrillation who seem likely to fall and sustain an intracra-
discharge medications. Chart abstractors were unaware of
nial hemorrhage. Epidemiological studies have found that
antithrombotic therapy can double the risk of intracranialespecially fatal Thus, accurate
knowledge of the rate of intracranial hemorrhage in patientsat high risk for falls with atrial fibrillation would help
Intracranial hemorrhage and ischemic strokes in the fol-
determine the optimal antithrombotic therapy.
low-up period were identified by recently validated ICD-9
Our primary goal was to quantify the incidence of intra-
codes in Medicare Part A data. We identified ischemic
cranial hemorrhage in Medicare beneficiaries with atrial
stroke from ICD-9 codes 433.x1, 434.x1, 436, 437.1, and
fibrillation who were at high risk of falls. Our secondary
437.9 (“x” represents any digit) in any position. As com-
goals were to identify independent risk factors for intracra-
pared to structured chart abstraction, these codes have a
nial hemorrhage and to quantify the benefits of warfarin
positive predictive value of We identified nontrau-
therapy, if any, in patients at high risk for falls.
matic intracranial hemorrhages from codes 430x– 432x andtraumatic intracranial hemorrhage from codes 800.2x,800.3x, 800.7x, 800.8x, 801.2x, 801.3x, 801.7x, 801.8x,
803.2x, 803.3x, 803.7x, 803.7x, 804.2x, 804.3x, 804.7x,804.8x, 852, and 853. The positive predictive value of these
The primary endpoint was hospitalization for an intra-
ICD-9 codes for intracranial hemorrhage is
cranial hemorrhage after the index hospital admission. The
In a subgroup analysis we identified myocardial infarc-
study was approved by the Washington University human
tion from ICD-9 code 410.x and noncerebral hemorrhage
based on ICD-9 codes validated by White et Weassessed predictive validity of the high-fall-risk designation
Formation of the second national registry of
using Medicare Part A and B claims by assessing for falls
(E880.0-E886.9, E888) and fractures (800-829).
In the primary analysis we censored patients at the time
The National Registry of Atrial Fibrillation II dataset
of their last hospitalization if they died outside of the hos-
was created from 23 657 anonymous patient records gath-
pital because neither Medicare Part A or B claims nor the
ered by Quality Improvement Organizations for the Na-
Medicare Denominator File provides cause of death. Like-
tional Stroke Project. The project was managed by the Iowa
wise, those who died after the baseline hospitalization (be-
Foundation for Medical Care. The dataset included both
fore another hospitalization) were excluded (n ϭ 1824). In
Medicare records and chart-abstracted data from 3586 hos-
a secondary analysis, we included out-of-hospital deaths as
pitals in all 50 US states. Medical records were selected as
part of a composite endpoint that also included stroke,intracranial hemorrhage, and myocardial infarction. Forbeneficiaries who experienced multiple adverse events, we
Supported by the American Heart Association
The conclusions presented are solely those of the
excluded events and days of follow-up that occurred after
authors and do not represent those of the Quality Improvement Organiza-
tions, American Heart Association, or CMS. The content of this publicationdoes not necessarily reflect the views or policies of the Department ofHealth and Human Services, nor does mention of commercial products
imply endorsement of them by the U. S. Government. The authors assumefull responsibility for the accuracy and completeness of the ideas presented.
The only acceptable source of information for risk of
Requests for reprints should be sent to: Brian F. Gage, MD, MSc,
falls was physician documentation in the medical record.
Division of General Medical Sciences, Washington University School of
The terms “frequent falls,” “history of falls,” “multiple
Medicine Campus Box 8005, 660 S. Euclid Ave., St. Louis, MO 63110.
falls,” or “tendency for falls” were considered synonymous
The American Journal of Medicine, Vol 118, No 6, June 2005
with high risk for falls; a single fall was insufficient docu-
Demographic and clinical factors of study cohorts
mentation for this designation. We also identified a trial-likecohort comprising patients who lacked the following co-
morbid conditions: high risk for falls, age 80 or older,
chronic renal disease, uncontrolled hypertension, malig-
nancy, alcoholism, history of bleeding, neuropsychiatric
impairment, prior ischemic stroke or transient ischemic at-
tack (TIA), anemia, bleeding disorder, and combination
therapy with warfarin and aspirin at discharge.
We used time-to-event analyses to test our hypotheses
that the risks of intracranial hemorrhage and of stroke were
greater in patients at high risk for falls. We used backward
elimination to develop parsimonious Cox models. We ver-
ified the proportionality assumption graphically and by
time-dependent covariates. In the intracranial hemorrhage
model, we tested for effects of history of ischemic stroke or
TIA, age, sex, race, alcoholism, history of bleeding, a bleed-
ing disorder (eg, hemophilia or leukemia), nursing home
residence, neuropsychiatric impairment (schizophrenia, de-
mentia, or Parkinson’s disease), and antithrombotic therapy.
In the ischemic stroke Cox model, we tested for effects of
sex, nursing home residence, antithrombotic therapy, and
stroke factors. We quantified the risk of stroke using a
clinical prediction (CHADS ) that assigns 1 point for the
presence of Congestive heart failure, Hypertension, Age Ͼ
75, or Diabetes mellitus, and 2 points for a prior Stroke or
In a subgroup analysis, we initially stratified the
analysis into CHADS scores of 0 –1, 2, or 3– 6, because the
benefit of warfarin therapy is greater in patients with atrialfibrillation at greater risk of Because the apparentbenefit of warfarin was similar in patients with 2 points and
were coded after the baseline hospitalization. Compared to
with 3– 6 points, we combined these two cohorts.
other patients, patients at high risk for falls were 2.0 (95%
Statistical tests were two-tailed. We performed statistical
CI: 1.6 –2.4) times more likely to fall. The rates of fractures
analyses in SAS version 9.0 (SAS Institute Inc; Cary, NC).
per 100 patient-years were 27.9 in patients at high risk forfalls and 12.0 in other patients.
The rates of intracranial hemorrhage per 100
patient-years were 2.8 (95% CI: 1.9 – 4.1) in patients at high
Subjects at high risk for falls were older and had more
risk for falls and 1.1 (95% CI: 1.0 –1.3) in other patients (P
comorbidities than other patients. In addition, they were
Ͻ 0.0001, log-rank test). In the subset of the trial-like
significantly less likely to receive warfarin or aspirin ther-
patients, the rate of intracranial hemorrhage was 0.53 (95%
CI: 0.3– 0.8). The rates of traumatic intracranial hemorrhage
Trial-like patients (n ϭ 3236) were younger (mean age,
per 100 patient-years were 2.0 (95% CI: 1.3–3.1) in patients
73 years) and healthier (mean number of bleeding risk
at high risk for falls and 0.34 (95% CI: 0.27– 0.45) in other
factors, 0.6). Most of them were prescribed antithrombotic
Ͻ 0.0001, log-rank test).
therapy (53.7% warfarin; 23.1% aspirin).
In the multivariate Cox model patients at high
risk for falls were 1.9 (95% CI 1.3–2.9) times more likely to
Data integrity and validation
have any intracranial hemorrhage and 4.1 (95% CI 2.4 –7.1)times more likely to have a traumatic intracranial hemor-
We validated the fall-risk designation by examining
rhage than other patients. Prior stroke (HR 2.2), prior major
ICD-9 codes for falling and for nonpathologic fractures that
bleeding (HR 1.8), and neuropsychiatric impairment (HR
Risk of Intracranial Hemorrhage in Patients Prone to Fall
1.4) also were independently associated with any intracra-
Multivariate Cox regression showing hazard ratios
nial hemorrhage Prescription of warfarin or as-
(HR) of independent predictors of intracranial hemorrhage
pirin at baseline did not significantly affect risk of intracra-nial hemorrhage: the HR for warfarin was 1.0 (95% CI
0.8 –1.4) and the HR for aspirin was 1.1 (95% CI 0.8 –1.4).
Alcohol abuse, non-Caucasian race, bleeding disorder, and
renal disease were too infrequent in the dataset to quantify
After an intracranial hemorrhage, 30-day mortality was
42% in patients at high risk of falls and 48.2% in otherpatients (P
Ͼ 0.2). The intracranial hemorrhage 30-day
Risks and benefits of warfarin therapy in patients
mortality was 51.8% in patients who had been prescribed
at high risk for falls
warfarin, and 33.6% in patients who had not been pre-scribed warfarin after the baseline hospitalization (P
To determine the potential benefit of prescribing warfa-
0.007). In a stepwise logistic regression model, the only
rin in patients at high risk for falls, we quantified the
independent predictors of 30-day mortality post intracranial
association between warfarin use and the composite out-
hemorrhage were prior prescription of warfarin (odds ratio
come of hospitalization for stroke, any hemorrhage (includ-
2.5; 95% CI 1.4 – 4.5, P
ϭ 0.002) and nursing home resi-
ing intracranial hemorrhage), myocardial infarction, or out-
dency (odds ratio 3.3; 95% CI 1.6 – 6.8, P
of-hospital death (except in patients with terminal disease).
In the Cox model that controlled for bleeding risk factors,aspirin prescription, nursing home residency, and sex, war-
farin was significantly protective in 1086 patients with 2 ormore CHADS points (HR 0.75), but not protective in 159
Stroke rates (95% CI) per 100 patient-years were 13.7
patients with 0 or 1 points in (HR 0.98) The
(11.6 –16.3) in patients at high risk for falls and 6.9 (6.5–
-value for interaction between warfarin and stroke risk was
7.3) in other patients. In the subset of the trial-like patients,
the stroke rate was 2.8 (95% CI: 2.3–3.4). Compared toother patients, patients at high risk for falls had a 1.3-fold(95% CI: 1.1–1.6) increased risk of stroke (P
Each 1-point increase in the CHADS score increased the
risk of stroke by a factor of 1.42 (95% CI: 1.37–1.47, P
Despite their low use of warfarin (33.5%), patients at
0.0001). Hazard ratios (HR) and 95% CI of other indepen-
high risk for falls suffered 2.8 intracranial hemorrhages per
dent stroke risk factors were neuropsychiatric impairment
100 patient-years, more than twice the 1.1 intracranial hem-
1.22 (1.06 –1.40, P
ϭ 0.05) and nursing home residence
orrhage rate of other participants and more than 5 times the
1.45 (1.29 –1.64, P
Ͻ0.0001); warfarin prescription at hos-
0.5 rate of trial-like participants. The increased risk of
pital discharge had a modestly protective effect 0.78 (0.70 –
intracranial hemorrhage in patients at high risk for falls was
Ͻ0.0001). After stroke, 30-day mortality was 34.4%
due to their increased incidence of traumatic intracranial
among high-fall-risk subjects, 27.8% in other patients, and
hemorrhage, which was increased four-fold compared to
other patients, even after adjusting for the covariates. The30-day mortality after an intracranial hemorrhage was sig-
Hazard ratio of warfarin for composite outcome—
Rates of intracranial hemorrhage, stratified by
out-of-hospital death or hospitalization for stroke,
myocardial infarction, or hemorrhage—in 1245 patients athigh risk for falls
Intracranial hemorrhage rate (95% CI) per 100 patient-years
CHADS stroke score was calculated by adding 1 point for each of
the following conditions: congestive heart failure, hypertension, ageϾ 75 years, or diabetes and 2 points for a prior stroke or transient
Ͻ 0.0001 High-fall vs other patients.
ischemic attack. CI indicates confidence interval.
ϭ 0.0005 High-fall vs other patients.
The American Journal of Medicine, Vol 118, No 6, June 2005
nificantly greater in patients who had been prescribed war-
what antithrombotic therapy was prescribed at hospital dis-
farin after the baseline hospitalization (51.8%) than in pa-
charge but did not capture subsequent initiation or discon-
tients who had not been prescribed warfarin (33.6%). These
tinuation of therapy. Thus, the observed lack of association
observations highlight the substantial risk and mortality of
between warfarin and intracranial hemorrhage in this study
intracranial hemorrhage in populations who are older and
does not refute such an A third limitation is
frailer than carefully selected trial participants.
that we had to exclude patients who died after the baseline
Despite the significant association between intracranial
hospitalization and without another hospitalization because
hemorrhage and fall risk, the findings support the use of
they had no follow-up data. A minor limitation was that we
anticoagulants in patients at high risk for falls who are at
could not evaluate risk factors for intracranial hemorrhage
moderate to high risk of stroke. Prescribing warfarin in
that were unavailable (eg, leukoaraiosis on brain imaging or
patients at high risk for falls with 2 or more CHADS points
tobacco use). Likewise, we used physician documentation
was associated was a 25% relative risk reduction (HR 0.75)
to ascertain risk of falls and were unable to evaluate the risk
in the composite outcome When prescribing
of specific impairments in strength, balance, vision, or or-
warfarin to these patients, providers could instruct them to
take precautions to limit their risk of falling: wear stable
These limitations are offset by several strengths. First,
the cohort design allowed us to calculate incidence rates and
aids,and discontinue unnecessary medications.
to avoid recall bias. Second, we were able to use structured
In contrast to the potential benefits of warfarin in patients
medical record abstraction to adjust for potential confound-
with greater CHADS scores, prescribing warfarin in pa-
ing factors. Third, the large size and national sample of the
tients at high risk for falls with 0 or 1 CHADS points was
dataset provide great generalizability. Fourth, the designa-
associated with a nonsignificant reduction in the composite
tion “high-fall-risk” predicted subsequent fractures and
outcome Because the 95% confidence interval of
falls, validating the designation. The specificity between therelationship between high-fall-risk and traumatic intracra-
the HR (0.98) was wide (0.59 –1.72), warfarin could either
nial hemorrhage validates the association.
be beneficial or harmful in this population. Given this un-
In summary, patients at high risk for falls are at substan-
certainty and the known expense, hassle, and risks of war-
tially increased risk of intracranial hemorrhage, especially
farin therapy, we recommend aspirin or no antithrombotic
traumatic intracranial hemorrhage. However, because of
their increased risk of stroke, they appear to benefit from
Besides fall risk, prior stroke, prior bleeding, and neuro-
anticoagulant therapy if they have atrial fibrillation and at
psychiatric impairment were associated with incident intra-
cranial hemorrhage. Others also have found an association
between prior stroke and intracranial Themechanism behind this association may be loss of micro-vascular integrity or disruption of neurovascular homeosta-
sis. Patients with a history of epistaxis are more likely tohave an intracranial and patients with a prior
The authors appreciate the assistance of the Iowa Foun-
intracranial hemorrhage, especially a primary lobar intra-
dation for Medical Care, the other Quality Improvement
cranial hemorrhage, are at increased risk of
Organizations, and the Centers for Medicare & Medicaid
The association between intracranial hemorrhage and neu-
Services (CMS) in providing data that made this research
ropsychiatric disease may depend on the type of neuropsy-
chiatric disease and the degree of impairment in perfor-mance Psychiatric disease may cause falls becauseof treatment with psychotropic associated
alcohol use, or poor compliance. Patients with Parkinson’sdisease can fall because of a festinating Patients with
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Montag, 4. Juni 2007 G R A U B Ü N D E N Vielfältige Unterstützung für das Calancatal Über das Wochenende ist es im Calancatal zu «Wir haben gesehen, kleinerenAbbrüchen in der kritischen Felsmas-se oberhalb des Steinbruchs von Arvigo ge-kommen. Bis gestern Abend konnte der nördli-che Teil des Tals durch die Felssturzgefahr nurper Heli erreicht werden. Seit Samstag ist nu
Las municipalidades, con el objeto de promover la salud y el desarrollo comunal, pueden implementar nuevas prestaciones de salud, insertas en planes comunales de esa naturaleza, en los casos en que no exista política pública ministerial, en la medida que tales prestaciones sean financiadas directamente por el paciente particular o haciéndose cargo el propio municipio de asumir su costo y no se