ORIGINAL INVESTIGATION

Choosing Antithrombotic Therapy

for Elderly Patients With Atrial Fibrillation
Who Are at Risk for Falls
Malcolm Man-Son-Hing, MD, MSc, FRCPC; Graham Nichol, MD, MPH, FRCPC;
Anita Lau; Andreas Laupacis, MD, MSc, FRCPC

Objective: To determine whether the risk of falling (with
a possible increased chance of subdural hematoma) should
influence the choice of antithrombotic therapy in el-
derly patients with atrial fibrillation.
Design: A Markov decision analytic model was used to
determine the preferred treatment strategy (no anti-
thrombotic therapy, long-term aspirin use, or long-
term warfarin use) for patients with atrial fibrillation who
are 65 years of age and older, are at risk for falling, and
have no other contraindications to antithrombotic therapy.
Input data were obtained by systematic review of MED-
LINE. Outcomes were expressed as quality-adjusted life-
years.
falling, warfarin therapy was associated with 12.90 quality-
adjusted life-years per patient; aspirin therapy, 11.17 qual-
ity-adjusted life-years; and no antithrombotic therapy,
10.15 quality-adjusted life-years. Sensitivity analysis dem-
onstrated that, regardless of the patients’ age or baseline
risk of stroke, the risk of falling was not an important
factor in determining their optimal antithrombotic
therapy.
Conclusions: For elderly patients with atrial fibrilla-
tion, the choice of optimal therapy to prevent stroke de-
pends on many clinical factors, especially their baseline
risk of stroke. However, patients’ propensity to fall is not
an important factor in this decision.

Results: For patients with average risks of stroke and Arch Intern Med. 1999;159:677-685

From the Department of
Medicine, University of Ottawa
(Drs Man-Son-Hing, Nichol,
and Laupacis), and the Clinical
Epidemiology Unit
(Drs Man-Son-Hing, Nichol,
and Laupacis and Ms Lau) and
Geriatric Assessment Unit
(Dr Man-Son-Hing), Ottawa
Hospital, Ottawa, Ontario.
Dr Nichol is a Career Scientist
of the Ontario Ministry of
Health. Dr Laupacis is a Career
Scientist of the Medical
Research Council of Canada.
A
PPROXIMATELY 5% of per-
sons 65 years of age and
older have atrial fibrilla-
tion.1 Their average yearly
risk of stroke is 5%, and
this risk is increased in the presence of cer-
tain risk factors, including left ventricular
dysfunction, hypertension, a history of
stroke, and increasing age.2 Long-term an-
tithrombotic therapy with warfarin or as-
pirin reduces these patients’ chance of
stroke by 68%2 and 21%,3 respectively.
There is no convincing evidence that these
relative risk reductions vary according to
patients’ baseline chance of stroke. There-
fore, among all age groups, elderly per-
sons receive the greatest absolute benefit
from warfarin or aspirin prophylaxis. In fact,
an expert panel recommended that all el-
derly persons with atrial fibrillation should
be considered for long-term warfarin
therapy unless a contraindication exists.4
Balanced against this benefit is the
risk of antithrombotic-associated, life-
threatening bleeding complications, in-
cluding subdural hematomas (SDHs) and
intracerebral hemorrhages. These compli-
cations also increase with age.5 Trauma to
the head (often due to falls) may also be
an etiologic factor in the development of
SDHs.6 For this reason, many studies7-9
evaluating the effectiveness and appropri-
ateness of warfarin therapy in patients with
atrial fibrillation have excluded subjects
with a predisposition to falls. Also, other
studies10,11 have implicated aspirin use as
a risk factor for development of SDHs in
patients with head trauma. Thus, many
physicians are reluctant to prescribe an-
tithrombotic therapy (especially warfa-
rin) for elderly patients with atrial fibril-
lation whom they deem at risk for falls.12
The objective of this decision analysis was
to compare the benefits and risks of anti-
thrombotic therapy (either warfarin or as-
pirin) in community-living, elderly per-
sons with atrial fibrillation based on their
risk of falls.
RESULTS
Of 190 relevant scientific studies re-
viewed, 49 met the inclusion criteria. In-
tracranial hemorrhages (both SDHs and in-
tracerebral hemorrhages) were exceedingly
uncommon events in prospective cohort

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 METHODS
THE DECISION MODEL
A decision analytic model was constructed to describe the
possible outcomes of 3 different treatment strategies for el-
derly persons with atrial fibrillation who may be at risk for
falling: (1) warfarin therapy, then switch to aspirin in the
event of a nonfatal, non–central nervous system (non-
CNS) major bleeding episode; (2) aspirin therapy, then switch
to warfarin in the event of a transient ischemic attack or re-
versible ischemic neurologic deficit; and (3) no treatment,
then switch to aspirin in the event of a transient ischemic
attack or reversible ischemic neurologic deficit. An age-
specific standardized mortality table was used to model the
chance of all-cause mortality. Outcomes were expressed in
terms of quality-adjusted life years (QALYs) for patients 65
years of age at the starting point of the analysis. All life-
years were discounted at the rate of 3% per annum.
Markov subtrees with identical structures were used
to model the chance events associated with the 3 treat-
ment strategies (Figure). Probability of each event was based
on a systematic review of the published literature. The
Markov cycle length was fixed at 3 months, with all rel-
evant probabilities and utilities adjusted to reflect this cycle
length. Results of the analysis were reported for a 1-year
period.
OUTCOMES
The 5 states considered in the analysis were based on the
work of Gage et al13 in describing disability states after stroke:
1. Well: the state for patients who had no adverse
events such as stroke, intracranial hemorrhage (SDH and
intracerebral hemorrhage), and major non-CNS bleeding.
The well state was the starting point for all patients;
2. Minor disability (modified Rankin Scale14 score 1
or 2 stroke): mild residual neurologic deficit (eg, mild right-
sided arm and leg weakness but remaining essentially func-
tionally independent);
3. Moderate disability (modified Rankin Scale14 score
3 or 4 stroke): moderate neurologic deficit (eg, right arm
and leg weakness sufficient to require assistance for some
studies that examined the incidence and consequences of
falls in community-living, elderly persons. Because of this
rarity, most information pertaining to risk and outcomes
of SDHs and intracerebral hemorrhages was obtained from
prospective cohort studies of patients treated at antico-
agulation clinics, and retrospective case series (Table 2).
STROKE
Probability of Events
The meta-analyses2,3 (pooling of individual patient data
from 5 randomized controlled trials) of the Atrial Fibril-
lation Investigators (AFI) were used to estimate the prob-
ability of stroke in elderly patients with atrial fibrilla-
tion who received no therapy, aspirin, or warfarin. Because
the AFI did not specifically publish data for subjects 65
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functional activities, including bathing and dressing, but
having independent ambulation with a walker or cane);
4. Major disability (modified Rankin Scale14 score 5
or 6 stroke): severe neurologic deficit (eg, total paralysis
of the right arm and leg requiring almost total care with
functional activities, including help with ambulation and
feeding); and
5. Dead.
INPUT DATA
Search Strategy
Relevant data for input variables were gathered by per-
forming a systematic literature search using the MED-
LINE (1966 to August 1996) computerized database. Rel-
evant articles were identified by using the following key
words: accidental falls, anticoagulants, cerebral hemor-
rhage, subdural hematoma, aspirin, warfarin, cerebral he-
matoma, atrial fibrillation, outcome assessment (health care),
treatment outcome, prognosis, and risk factors. The bibliog-
raphies of each article were hand searched to identify ad-
ditional articles. Content experts were also consulted to iden-
tify other relevant published work.
Development of Article Inclusion Criteria
After initial review of the methodologic quality of studies
available to estimate input variables, general criteria were
developed for inclusion of studies into the decision analy-
sis (Table 1). The appropriate set of criteria was applied
to each article by 2 individuals (M.M.-S.-H. and A. Lau),
with any disagreements settled by collaborative review.
Data Extraction and Pooling of Results
For each input variable, we extracted relevant information
from each study that met the inclusion criteria. We prefer-
entially sought data pertaining to persons 65 years and older.
Point estimates for input variables were determined by arith-
metic pooling of the results from all studies that met the in-
clusion criteria. Data extraction was performed indepen-
dently by 2 individuals (M.M.-S.-H. and A. Lau), with any
disagreements settled by collaborative review.
years of age and older, we requested and received this
information from the investigators. Based on approxi-
mately 2000 patient-years of follow-up, the annual stroke
rate was 6% for patients receiving no therapy. From the
AFI meta-analyses,2,3 aspirin and warfarin provided 21%
and 68% relative risk reductions, respectively.
The annual risk of persons having a transient ische-
mic attack or reversible ischemic neurologic deficit was
assumed to be one third the rate of stroke for all groups.2
For persons having a stroke (either minor or major), their
subsequent relative risk of having a second stroke was
estimated at 3.1 times their prestroke rate.2
Outcomes
For persons having a stroke, the proportions who had
fatal, major, or minor strokes were also estimated
 A Table 1. General Inclusion Criteria*
No Treatment
Markov Subtree

Aspirin Related Variables: Inclusion Criteria

Initial Therapy Markov Subtree

Warfarin
Stroke (probabilities and outcomes)
Markov Subtree Major non-CNS bleeding
(probabilities and outcomes) Randomized controlled trial
B Die SDH and intracerebral hemorrhage
Subtree (probabilities)
Stroke and Intracranial Hemorrhage Falls (probability and Prospective cohort study
Subtree risk factors) Population
Second Intracranial Hemorrhage Representative sample
Subtree Age .60 y
Subdural Hematoma Females.males
Subtree Follow-up
Intracerebral Hemorrhage .90%
Subtree .48 wk
Second Stroke Multiple risk factors assessed
Markov Subtree Subtree SDH (outcomes) Consecutive case series
Major Stroke Intracerebral hemorrhage (outcomes) CT scan era
Subtree
Minor Stroke *Non-CNS indicates non–central nervous system; SDH, subdural
Subtree
hematoma; and CT, computed tomographic.
Non-CNS Bleeding
Subtree
Well
occurrence of the stroke; (2) major stroke (correspond-
Subtree ing closely to Rankin score 3-5 strokes); and (3) minor
Well, Switch Therapy
Subtree
stroke (corresponding closely to Rankin score 1-2
strokes). With no firm evidence that the chance of suf-
fering a fatal stroke varies with the type of antithrom-
C Fall
Subtree botic therapy used, patients suffering a stroke were
Die assigned an average fatality rate as determined from all
Dead
patients with stroke in the AFI studies. For major
Subdural Fatal strokes, the proportion of patients with moderate dis-
Dead
Hematoma ability (Rankin score 3) compared with major disability
Nonfatal Subdural (Rankin score 4-5) was unavailable. For simplicity,
Hematoma
patients having a major stroke were assigned a utility
Intracerebral Fatal
Dead
that was an average of the utilities of a moderate and
Well Subtree Hemorrhage major disability.
No Fall Nonfatal Intracerebral
Hemorrhage
SDH AND INTRACEREBRAL HEMORRHAGE
Fatal
Dead
Stroke Probability of Events
Major
Nonfatal Major Stroke
Minor Too few SDHs and intracerebral hemorrhages occurred dur-
Minor Stroke
ing the AFI studies to use these data to precisely estimate
Non-CNS Fatal the probability of such events when receiving no therapy,
Bleeding Dead

Nonfatal
Well
TIA/RIND
Well, Switch
Therapy
Well
Well
Schematic representation of the decision model. A, Basic structure of the
decision model. The square represents the choice of 3 treatment strategies:
no treatment, aspirin therapy, and warfarin therapy. B, Markov Subtree shows
11 health states for the 3 treatment options. Patients remain in the well state
until 1 of 6 adverse outcomes occur: stroke, subdural hematoma, intracere-
bral hemorrhage, major non–central nervous system (non-CNS) bleeding,
transient ischemic attack (TIA)/reversible ischemic neurologic deficit (RIND),
or death. Probability of these events depends on the prescribed therapy and
chance of falling. C, Well Subtree illustrates the adverse events. Circles repre-
sent chance outcomes. Boxes to the far right show the health states patients
enter if they experience an adverse outcome. Subtrees for other health states
(except death) have similar structures but are not shown.
from the AFI data.2 The AFI classified stroke as follows:
(1) fatal stroke, if the patient died within 1 month of
aspirin, or warfarin. Therefore, for persons who do not fall,
we estimated the probability of developing an SDH when
receiving no treatment from population studies15 and re-
view articles.11 The probability of SDHs when taking aspi-
rin or warfarin were estimated from randomized con-
trolled trials16 and anticoagulation clinic cohort studies,5,17-22
respectively. We again pooled results from population stud-
ies to estimate the probability of intracerebral hemor-
rhage when receiving no therapy,16,23,24 randomized con-
trolled trials16 when receiving aspirin, and anticoagulation
clinic cohort studies5,17-22 when receiving warfarin.
Outcomes
For persons with SDH and intracerebral hemorrhage, we
were unable to determine the likelihood of different out-
comes from the AFI data. Therefore, SDH and intracerebral
hemorrhage fatality rates when receiving no therapy15,23-32
and warfarin15,17,19,23,24,26-28,32-40 were estimated by pooling

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 Table 2. Input Data: Relevant Probabilities and Utilities* Table 2. Input Data: Relevant Probabilities and Utilities* (cont)

Base Base
Input Variable Case Source (Reference) Input Variable Case Source (Reference)
No Therapy Warfarin Therapy
Probability of (per Relative risk of (compared
patient-year): with no therapy):
Stroke 0.060 AFI (2, 3) Stroke 0.32 AFI (2, 3)
Fatal, % 26.7 AFI (2, 3) Fatal, % 26.7 AFI (2, 3)
Major, % 20.7 AFI (2, 3) Major, % 18.3 AFI (2, 3)
Minor, % 52.6 AFI (2, 3) Minor, % 55.0 AFI (2, 3)
Chance of (compared Subdural hematoma 3.25 Anticoagulation clinic cohort
with stroke rate): (5, 17-22)
TIA/RIND 0.3 AFI (2, 3) Fatal, % 25.4 Consecutive case series
Second stroke 3.1 AFI (2, 3) (13, 25, 32-35)
Subdural hematoma 0.0004 Population studies (11, 15) Intracerebral 7.5 Anticoagulation clinic cohort
Fatal, % 46.7 Consecutive case series hemorrhage (5, 17-22)
(15, 25, 26) Fatal, % 57.6 Consecutive case series
Intracerebral hemorrhage 0.001 Population studies (11, 23, 24) (15, 17, 19, 23, 24, 27,
Fatal, % 41.2 Consecutive case series 28, 32, 35-40)
(23, 24, 27-32) Non-CNS bleeding 1.5 AFI (2, 3)
Non-CNS bleeding 0.0117 AFI (2, 3) Fatal, % 14.9 Anticoagulation clinic cohort
Fatal, % 13.4 Antiplatelet trialists (41) (5, 17, 21, 42, 43)

Aspirin Therapy Falls

Relative risk of (compared Chance of fall (in 1 year) 0.33 Prospective cohort (44-50)
with no therapy): Relative risk of subdural 1.4 Derived (see text)
Stroke 0.79 AFI (2, 3) hematoma (compared
Fatal, % 26.7 AFI (2, 3) with persons who do
Major, % 31.0 AFI (2, 3) not fall)
Minor, % 42.3 AFI (2, 3) Utilities
Subdural hematoma 2.0 Hart et al (16) Well, taking
Fatal, % 46.7 Assumed (same as no therapy) No therapy 1.0 Definition
Intracerebral hemorrhage 2.0 Hart et al (16) Aspirin 0.998 Gage et al (13)
Fatal, % 41.2 Assumed (same as no therapy) Warfarin 0.987 Gage et al (13)
Non-CNS bleeding 1.2 AFI (2, 3) Disability
Fatal, % 4.8 Antiplatelet trialists (41) Minor 0.76 Gage et al (13)
Moderate 0.39 Gage et al (13)
Major 0.11 Gage et al (13)
TIA/RIND 0.76 Assumed (same as minor stroke)
studies that reported consecutive cases. For persons re- Dead 0.0 Definition
ceiving aspirin at the time of their SDH or intracerebral
hemorrhage, information about their outcomes was not *AFI indicates Atrial Fibrillation Investigators; TIA/RIND, transient ischemic
available. Therefore, we assumed that their probability of attack/reversible ischemic neurologic deficit; and CNS, central nervous system.
fatality was identical to persons receiving no therapy.
For persons who survived SDHs and intracerebral ity rates. For persons receiving no treatment or aspirin,
hemorrhages, data pertaining to the severity of their re- data from the Antiplatelet Trialists’ Collaboration41 were
sidual functional disability were not available. Thus, we as- used to estimate the proportion of those dying as a re-
sumed that a moderate disability occurred in all persons sult of a major non-CNS bleeding episode. For persons
who survived their SDH or intracerebral hemorrhage. receiving warfarin, we estimated the fatality rate from ma-
jor non-CNS bleeding from anticoagulation clinic co-
MAJOR NON-CNS BLEEDING hort studies.5,17,21,42,43 We assumed that all patients who
survived a major non-CNS bleeding episode returned to
Probability of Events their pre-event health state.

The probability of major non-CNS bleeding in patients FALLS

receiving no treatment, aspirin, and warfarin was esti-
mated from the AFI data.2 The AFI analysis defined ma-
jor bleeding as one requiring blood transfusion, an emer-
gency procedure, surgical intervention, or hospitalization.
For simplicity, minor bleeding episodes (eg, external
bruising, nosebleeds) were not modeled.
Outcomes
In the AFI, too few deaths occurred from major non-
CNS bleeding episodes to precisely estimate these fatal-
Probability and Risk Factors
Seven cohort studies44-50 that met the eligibility criteria
prospectively observed 2181 community-living, elderly
($65 years of age) persons for their rate and conse-
quences of falls. Thirty-three percent of these persons ex-
perienced at least 1 fall after 1 year of follow-up. Tinetti
and colleagues46 identified 6 major independent risk fac-
tors for falls: sedative use, cognitive impairment, disabil-
ity of the lower extremity, palmomental reflex, gait and

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balance abnormalities, and foot problems. For persons
with 1 risk factor, their chance of falling in 1 year was
19%; 2 risk factors, 32%; 3 risk factors, 60%; and 4 or
more risk factors, 78%.
Relative Risk of SDHs in Persons
Who Fall Compared With Those Who Do Not
The relative risk of SDHs in persons who fall was
derived from the following information: 70% of elderly
persons who develop an SDH have a history of head
trauma,15,26,35,51 and 50% of SDHs due to head trauma
are related to falls.24,26,51 Therefore, (a) 0.35 of SDHs
are related to falls (50% of the 70% of SDHs due to
head trauma); (b) 0.35 of SDHs are related to head
trauma without falls (the remaining 50% of the 70% of
SDHs due to head trauma); and (c) 0.30 of SDHs are
unrelated to head trauma as ascertained by history and
observation.
Given that one third (33%) of community-living, el-
derly persons fall in 1 year,44-50 and the rate of SDHs in
elderly persons is 0.0004 for every patient-year,5,17-22 we
calculated that the two thirds (67%) of the elderly popu-
lation who do not fall in a year experience 67% of the
SDHs related to (b) and (c) above: [0.67 3 (b+c)] =
0.00017; and the one third (33%) of the elderly popula-
tion who do fall in a year experience 100% of the SDHs
due to (a) and 33% of (b) and (c) above: a + [0.33 3 (b+c)]
= 0.00023.
Therefore, the derived relative risk of developing an
SDH in persons who fall compared with those who do
not is 1.4 (0.00023/0.00017).
Outcomes
For adverse outcomes other than SDH, there were no data
available to determine a possible etiologic role of falls in
their occurrence and outcomes. Therefore, we assumed
that the occurrence of falls does not affect the probabil-
ity and outcomes of stroke, transient ischemic attack or
reversible ischemic neurologic deficit, intracerebral hem-
orrhage, and major non-CNS bleeding.
UTILITIES
By interviewing 69 patients with atrial fibrillation, Gage
et al13 determined utilities for disabilities associated with
minor, moderate, and major strokes (Table 2). These utili-
ties were assigned to the corresponding Markov states
of mild, moderate, and major disability. Gage et al also
determined utilities for long-term aspirin and warfarin
use. By definition, the well state and death were as-
signed utilities of 1 and 0, respectively.
BASE-CASE ANALYSIS
The base-case analysis considered elderly persons with
atrial fibrillation with average risks of stroke (6% per year)
and falling (33% per year). The results showed that the
quality-adjusted life expectancy for these patients was
12.90 years with warfarin therapy, 11.17 years with as-
pirin therapy, and 10.15 years with no therapy.
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SENSITIVITY ANALYSES
Sensitivity analyses (Table 3) were performed to test
the robustness of the results to changes in values of the
base-case variables. We examined the influence of each
throughout its entire reasonable range.
Sensitivity analysis showed that the values for vari-
ables related to SDH had little influence on the base-case
scenario. For example, to switch the optimal choice of
therapy from warfarin to no therapy, the relative risk of
SDH must be at least 65-fold greater for persons receiv-
ing warfarin compared with those receiving no therapy.
The probability of falls also had no influence on
choice of optimal therapy. When the chance of falling
in 1 year was varied from no chance (0%) to certainty
(100%), warfarin remained the treatment associated with
the highest QALYs. For warfarin to not be the optimal
therapy, persons with an average fall risk must have a
535-fold greater risk of SDH compared with those who
do not fall.
The results of the analysis were most sensitive to the
probabilities related to intracerebral hemorrhage and non-
CNS bleeding. If the probability of intracerebral hemor-
rhage was 12-fold or greater than our base-case rate of
0.001 cases per patient-year, then warfarin was not the
preferred treatment option. Similarly, for warfarin to not
be the preferred treatment option, the relative risk of in-
tracerebral hemorrhage when taking warfarin com-
pared with no therapy must be 29-fold or greater. Also,
the base-case probability of major non-CNS bleeding when
receiving no therapy must be 14-fold greater for warfa-
rin to not be the preferred treatment strategy.
Varying the efficacy of aspirin and warfarin to pre-
vent stroke affected the choice of optimal treatment. With
the values of all other variables remaining constant, as-
pirin therapy was the preferred treatment choice if the
efficacy of warfarin was reduced from 68% to 26%. Con-
versely, if the efficacy of aspirin was increased from 21%
to 54% (all other values for variables remaining con-
stant), it was the preferred therapy.
We also varied the values for utilities throughout
their ranges. With values for all other variables remain-
ing constant, warfarin was the preferred option when the
utility of long-term warfarin therapy was 0.816 or higher.
In the study by Gage et al,13 only 1 of the 69 patients who
underwent formal utility assessment reported a utility
score for long-term warfarin use of less than 0.92. The
preferred treatment choice was insensitive to all other utili-
ties throughout their ranges.
For patients with baseline stroke rates of less than
1.2% per year, no therapy was the preferred treatment
option. If their baseline stroke rate was between 1.2% and
2.0% per year, aspirin was the preferred therapy. If their
baseline stroke rate was greater than 2.0% per year, war-
farin therapy was the preferred option. These results are
compatible with the recent American College of Chest
Physicians recommendations,4 which recognize that, as
baseline risk of stroke diminishes, the absolute benefit
of stroke prophylaxis provided by antithrombotic therapy
(especially warfarin) also decreases. Thus, the appropri-
ate antithrombotic therapy for individual patients de-
pends on their baseline risk of stroke, with low-risk in-
 Table 3. Sensitivity Analysis

Optimal Theory

Baseline Base-Case Analysis Low Stroke Risk

Variable* (Range) (6% per Year) (2% per Year)
Stroke Parameters
Probability of stroke (events per patient-year) 0.060 (0.0-0.50) 0.0-0.012 No therapy
0.012-0.020 Aspirin Same as base-case
0.020-0.50 Warfarin
RR of stroke while taking warfarin 0.32 (0.0-1.0) 0.0-0.74 Warfarin 0.0-0.35 Warfarin
0.74-1.0 Aspirin 0.35-1.0 Aspirin
RR of stroke while taking aspirin 0.79 (0.0-1.0) 0.0-0.46 Aspirin 0.0-0.77 Aspirin
0.46-1.0 Warfarin 0.77-1.0 Warfarin
RR of second stroke 3.1 (1-50) Warfarin 0.0-2.5 Aspirin
2.5-50 Warfarin
SDH Parameters
Probability of SDH (events per patient-year) 0.0004 (0.0-0.50) 0.0-0.040 Warfarin 0.0-0.008 Warfarin
0.040-0.50 No therapy 0.008-0.0024 Aspirin
0.0024-0.50 No therapy
RR of SDH while taking warfarin 3.5 (0-500) 0-65.5 Warfarin 0-4.6 Warfarin
65.5-500 Aspirin 4.6-327.0 Aspirin
327.0-500 No therapy
RR of SDH while taking aspirin 2.0 (0-500) Warfarin 0.0-1.1 Aspirin
1.1-500 Warfarin
RR of SDH from falling 1.4 (1-1000) 1-535.0 Warfarin 1.0-13.6 Warfarin
535.0-1000 No therapy 13.6-58.1 Aspirin
58.1-1000 No therapy
ICH Parameters
Probability of ICH (events per patient-year) 0.001 (0.0-0.50) 0.0-0.012 Warfarin 0.0-0.0012 Warfarin
0.012-0.016 Aspirin 0.0012-0.0028 Aspirin
0.016-0.50 No therapy 0.0028-0.50 No therapy
RR of ICH while taking warfarin 7.5 (1-1000) 1-29.8 Warfarin 0-7.9 Warfarin
29.8-1000 Aspirin 7.9-1000 Aspirin
RR of ICH while taking aspirin 2.0 (1-1000) Warfarin 1.0-1.6 Aspirin
1.6-1000 Warfarin
Non-CNS Bleeding Parameters
Probability of non-CNS bleeding (events per patient-year) 0.0117 (0.0-0.75) 0.0-0.680 Warfarin 0.0-0.036 Warfarin
0.680-0.75 No therapy† 0.036-0.060 Aspirin
0.060-0.75 No therapy
RR of non-CNS bleeding while taking warfarin 1.5 (1-60) 0.0-12.2 Warfarin 1-1.7 Warfarin
12.2-60 Aspirin 1.7-39.7 Aspirin
39.7-60 No therapy
RR of non-CNS bleeding while taking aspirin 1.2 (1-60) Warfarin Warfarin
Fall Parameters
Probability of falling (chance per year) 0.33 (0.0-1.0) Warfarin Warfarin
Utility Parameters
Long-term warfarin use 0.987 (0.0-1.0) 0.0-0.816 Aspirin 0.0-0.628 Aspirin
0.816 -1.0 Warfarin 0.628-1.0 Warfarin
Long-term aspirin use 0.998 (0.0-1.0) Warfarin† Warfarin
Minor disability 0.76 (0.0-1.0) Warfarin 0.0-0.88† Warfarin
0.88-1.0 Aspirin
Major disability 0.11 (0.0-1.0) Warfarin 0.0-0.40 Warfarin
0.40-1.0 Aspirin

*RR indicates relative risk (compared with no therapy); SDH, subdural hematoma; ICH, intracranial hemorrhage; and CNS, central nervous system.
†Intracerebral.

dividuals being less appropriate candidates for warfarin
therapy.
According to the AFI data and the American Col-
lege of Chest Physicians risk stratification scheme,4 all
persons with atrial fibrillation who are 65 years of age
and older have at least a 2% yearly risk of stroke. To
determine the influence of falls on the choice of anti-
thrombotic therapy in low-risk individuals, we repeated
our analysis for those with this baseline risk of stroke.
The results showed that warfarin was the preferred
therapy (14.21 QALYs with warfarin, 14.17 with aspirin,
and 13.98 with no therapy). At this low baseline risk of
stroke, as one would expect, the preferred choice of
therapy was very sensitive to variables related to SDH,
intracerebral hemorrhage, non-CNS bleeding, and utili-
ties (Table 3). However, even under these conditions,

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the probability of falling did not influence the choice of
optimal therapy.
Alternative Methods of Estimating the Rate of SDH,
Intracerebral Hemorrhage, and
Major Non-CNS Bleeding
A possible limitation of this study is the questionable ac-
curacy of our estimates of the probability of SDH (when
receiving no treatment, aspirin, or warfarin) in persons
who do not fall. Because these estimates were derived from
studies that did not exclude patients who fall, we may
have overestimated the risk of SDH in persons who do
not fall. Since the studies of AFI meta-analysis tended to
exclude patients deemed at risk for falls, these data may
more accurately reflect the probability of SDH in per-
sons who do not fall. However, relatively few patients were
enrolled in these trials, making precise estimation of the
probability of SDH and intracerebral hemorrhage diffi-
cult from this source. We used AFI data in an attempt to
confirm our base-case estimates of the probability of SDH
and intracerebral hemorrhage in persons who do not fall.
From the AFI data, we calculated the probability of SDH
and intracerebral hemorrhage in patients taking warfa-
rin as 0.0012 and 0.0028 per patient-year, respectively.
These results were similar to our base-case estimates of
SDH (0.0013 per patient-year; 95% confidence interval,
0.0080-0.0018) and intracerebral hemorrhage (0.0030 per
patient-year; 95% confidence interval, 0.0022-0.0038).
Substitution of AFI-derived values into the model had
no significant impact on the analysis.
Similarly, an alternate method of estimating the rate
of major non-CNS bleeding in persons receiving warfa-
rin was derived using data from cohort studies of pa-
tients who attended anticoagulation clinics.5,17,21,42,43 Pool-
ing the results from these studies produced a rate of 0.0176
major non-CNS bleeding events per patient-year (AFI rate,
0.0172 events per patient-year). Again, substitution of
this value into the model resulted in no change in the
choice of optimal therapy.
We also believed that the values for variables re-
lated to SDH in persons who fall and/or are taking aspi-
rin or warfarin may be unreliable. To obtain alternative
estimates for these variables, we surveyed 10 Canadian
geriatric medicine specialists. Their subjective mean es-
timate of the relative risk of SDH in elderly persons who
fall was 2.91 (95% confidence interval, 2.53-3.29) and
5.64 (95% confidence interval, 2.93-8.35) when taking
aspirin and warfarin, respectively. These values were again
substituted into the model and the analysis was re-
peated. No substantial effect on the results occurred with
these substitutions.
Patients 75 Years and Older
Most clinicians perceive that the risk of warfarin- and fall-
related SDH increases as elderly persons age. Certainly,
the chance of falling52 and warfarin-related non-CNS
bleeding5 increases as elderly persons age. Therefore, we
repeated our analysis with the start age increased from
65 to 75 years. To estimate the risk of stroke in this popu-
lation when following different therapies, we used AFI
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©1999 American Medical Association. All rights reserved.
data pertaining exclusively to subjects 75 years and older
(stroke rate when receiving no antithrombotic therapy
was 8% per patient-year). For this age group, no spe-
cific data were available to estimate pertinent probabili-
ties related to SDH, intracerebral hemorrhage, and ma-
jor non-CNS bleeding. Therefore, compared with the base-
case analysis, we arbitrarily tripled the estimated risks
of these events. The results showed that, even under such
unlikely conditions, warfarin therapy remained the pre-
ferred therapy (quality-adjusted life expectancy was 7.06
years with warfarin therapy, 6.52 years with aspirin
therapy, and 6.76 years with no therapy).
COMMENT
A decision to prescribe antithrombotic therapy (either
aspirin or warfarin) for elderly patients with atrial fibril-
lation balances the benefits of stroke prevention against
the risk of adverse effects and inconvenience of the
therapy. Many physicians assume that a combination of
warfarin therapy and head trauma due to falls leads to
an excessively high risk of SDH and choose not to pre-
scribe warfarin for elderly persons with atrial fibrilla-
tion whom they deem prone to falling. We performed this
decision analysis to ascertain whether this is reasonable
clinical practice.
The base-case analysis and sensitivity analyses sug-
gest that a history of and/or the presence of risk factors
for falls should not be considered important factors in
the decision whether to offer antithrombotic (especially
warfarin) therapy to elderly patients with atrial fibrilla-
tion. In persons taking warfarin, fall-related SDHs are ex-
tremely infrequent. For elderly patients with atrial fibril-
lation with an average risk of stroke (6% per year), the
chance of this complication is completely overshad-
owed by the benefit of stroke protection provided by
warfarin.
Our results are consistent with previous studies ex-
amining the effectiveness of stroke prophylaxis in el-
derly patients with atrial fibrillation. In another deci-
sion analysis, Naglie and Detsky53 calculated a small net
gain in QALYs with the use of warfarin over aspirin and
no therapy. However, they overestimated the effective-
ness of aspirin, which was not known at the time of their
study. Gage and colleagues54 recently reported that war-
farin is also cost-effective in this population. In general,
our results agree with findings of earlier studies,55,56 with
differences, if they exist, due to previously imprecise es-
timates of the efficacy of aspirin.
It is possible to calculate the number of falls that per-
sons must have for warfarin to not be the optimal choice
of therapy. Elderly persons who fall have a mean of 1.81
falls per year.46 Given that the risk of SDH must be 535-
fold or greater for the risks of warfarin therapy to out-
weigh the benefits, persons taking warfarin must fall about
295 (535/1.81) times in 1 year for warfarin to not be the
optimal therapy. Since approximately 1 in 10 falls causes
major injury, including fractures,46-50,57,58 persons who fall
are much more likely to suffer other serious morbidity
before developing an SDH.
A major threat to the validity to this study is a pos-
sible inaccuracy of the input variables derived from the
literature. The sensitivity analysis showed that the base-
case analysis was robust to all values for variables related
to SDHs, falls, and warfarin therapy. Interestingly, this
analysis was most sensitive to values for variables related
to intracerebral hemorrhage and major non-CNS bleed-
ing. Our data suggest that warfarin-related intracerebral
hemorrhage and major non-CNS bleeding episodes are
more common events than warfarin-related SDH (with or
without falls). The infrequency of SDH in patients who
are receiving warfarin (whether they fall or not) accounts
for the robustness of the analysis. However, even after pe-
rusing the results of this study, one may still wonder if fall-
related SDHs are truly as rare as this analysis suggests. Fur-
ther evidence supporting the rarity of fall-related SDHs
comes from prospective cohort studies46-48,50,57,58 that ex-
amined the rate of falls and their outcomes in community-
living, elderly persons. Pooling these studies (n = 6) showed
that, from a total of 2590 falls, only 1 fall-related intracra-
nial hemorrhage (0 intracerebral hemorrhage and 1 SDH)
occurred. Why then do clinicians appear to overestimate
the risk of and occurrence of fall-related SDHs? A likely
explanation is that the occurrence of a fall-related SDH in
elderly patients is a rare but dramatic event that clini-
cians easily remember.
Another potential source of error in this decision
analysis is the possibility that the combination of war-
farin therapy and falls may lead to adverse outcomes (other
than SDH) for which we did not account. For example,
do falls have an etiologic role in the development of in-
tracerebral hemorrhage? Also, do elderly persons tak-
ing warfarin who have hip fractures experience excess
morbidity and mortality? We were unable to identify pub-
lished literature pertaining to these issues.
Two other notes of caution are appropriate. Clini-
cally important factors such as recent serious gastroin-
testinal tract bleeding, alcoholism, nonsteroidal anti-
inflammatory drug use, medication noncompliance, and
improper monitoring of patients’ anticoagulation status
increase the chance of warfarin-related serious bleed-
ing. These factors were not studied in this decision analy-
sis and must be considered in the clinical decision about
whether to offer antithrombotic therapy to individual el-
derly persons with atrial fibrillation. Also, the values for
stroke rates and subsequent outcomes used in this model
were derived from randomized controlled trials during
which subjects were observed more intensively than in
usual clinical practice. Thus, in these trials compared with
usual clinical practice, it is possible that the benefits and
complications of antithrombotic therapy were overesti-
mated and underestimated, respectively. Therefore, while
the sensitivity analysis appeared robust, in-depth discus-
sion with individual patients about the benefits and risks
of antithrombotic therapy is still very important, and some
caution may be necessary when applying the results of
this study to usual care settings.
In summary, this study demonstrates that the risk
of falling is not an important factor in the decision about
whether to offer antithrombotic therapy to elderly pa-
tients with atrial fibrillation. Of all age groups with atrial
fibrillation, patients 65 years and older gain the greatest
absolute benefit from warfarin prophylaxis. Numerous
studies59-62 have shown that many eligible patients with
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©1999 American Medical Association. All rights reserved.
atrial fibrillation (especially older persons) are not be-
ing prescribed warfarin. Clinicians must realize that the
propensity to fall is not a contraindication to the use of
antithrombotic agents (especially warfarin) in elderly per-
sons with atrial fibrillation.
Accepted for publication August 4, 1998.
We thank the Atrial Fibrillation Investigators for pro-
viding and Ruth McBride for tabulating unpublished AFI data.
We also thank Robert Hart, MD, Brian Gage, MD, Ron
Sigal, MD, and George Wells, PhD, for their helpful comments.
Reprints:Malcolm Man-Son-Hing, MD, MSc, FRCPC,
Geriatric Assessment Unit, Ottawa Hospital, 1053 Carling
Ave, Ottawa, Ontario, Canada K1Y 4E9 (e-mail:
mhing@civich.ottawa.on.ca).
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