Journal of the American College of Cardiology

2010 by the American College of Cardiology Foundation

Published by Elsevier Inc.

Vol. 56, No. 11, 2010

ISSN 0735-1097/$36.00
doi:10.1016/j.jacc.2010.05.028

STATE-OF-THE-ART PAPER

Age as a Risk Factor for

Stroke in Atrial Fibrillation Patients
Implications for Thromboprophylaxis
Ricarda Marinigh, MD,* Gregory Y. H. Lip, MD,* Nicola Fiotti, PHD, Carlo Giansante, PHD,
Deirdre A. Lane, PHD*
Birmingham, United Kingdom; and Trieste, Italy
The prevalence of atrial fibrillation (AF) is related to age and is projected to rise exponentially as the population
ages and the prevalence of cardiovascular risk factors increases. The risk of ischemic stroke is significantly increased in AF patients, and there is evidence of a graded increased risk of stroke associated with advancing
age. Oral anticoagulation (OAC) is far more effective than antiplatelet agents at reducing stroke risk in patients
with AF. Therefore, increasing numbers of elderly patients are candidates for, and could benefit from, the use of
anticoagulants. However, elderly people with AF are less likely to receive OAC therapy. This is mainly due to concerns about a higher risk of OAC-associated hemorrhage in the elderly population. Until recently, older patients
were under-represented in randomized controlled trials of OAC versus placebo or antiplatelet therapy, and therefore the evidence base for the value of OAC in the elderly population was not known. However, analyses of the
available trial data indicate that the expected net clinical benefit of warfarin therapy is highest among patients
with the highest untreated risk for stroke, which includes the oldest age category. An important caveat with warfarin treatment is maintenance of a therapeutic international normalized ratio, regardless of the age of the patient, where time in therapeutic range should be 65%. Therefore, age alone should not prevent prescription of
OAC in elderly patients, given an appropriate stroke and bleeding risk stratification. (J Am Coll Cardiol 2010;
56:82737) 2010 by the American College of Cardiology Foundation

Atrial fibrillation (AF) is a common cardiac arrhythmia that

confers substantial mortality and morbidity from stroke,
thromboembolism, and heart failure, and a significant impairment of quality of life (1,2). The prevalence of AF
increases markedly with older age (3,4): about 5% of people
over 65 years and 10% of people age 80 years suffer from
AF (4). The lifetime risk of AF is approximately 1 in 4
among people age 40 years and older (2,5). AF is more
prevalent in men than in women, although the absolute
number of women and men with AF is similar, given that
women outnumber men in the older age groups (6). The
prevalence of AF is projected to rise exponentially as the
population ages and the prevalence of cardiovascular risk
factors increases (4).
From the *University of Birmingham Centre for Cardiovascular Sciences, City
Hospital, Birmingham, United Kingdom; University of Trieste, Cardiology Department, Cattinara Hospital, Trieste, Italy; and the Istituto di Clinica Medica Generale
e Terapia Medica, University of Trieste, Trieste, Italy. Prof. Lip has served as a
consultant for Bayer, Astellas, Merck, AstraZeneca, Sanofi, Aryx, Portola, Biotronic,
and Boehringer, and has been on the Speakers Bureau for Bayer, Boehringer, and
Sanofi. Dr. Lane is in receipt of an investigator-initiated educational grant from Bayer
Healthcare, and has received industry-funded sponsorship for travel to cardiology
conferences. All other authors have reported that they do not have any relationships
to disclose.
Manuscript received January 1, 2010; revised manuscript received April 30, 2010,
accepted May 4, 2010.

AF is a major risk factor for stroke, increasing the risk of

ischemic stroke by approximately 5-fold (6), with approximately 15% of all strokes in the U.S. being attributable to
AF (6). Further, age is also a risk factor for stroke, with the
lifetime probability of suffering a stroke increasing steadily
with age, from 5.9% at 55 to 59 years, to 22.3% at 80 to 84
years in men, and from 3.0% to 23.9% over this age range in
women (1). Therefore, the combination of increasing age
and AF means that stroke prevention in elderly people with
AF is paramount.
The objective of this systematic review is to provide an
overview of published studies that have examined the
relation between age and stroke/thromboembolism in AF.
We appreciate that perioperative AF is also an important
predictor of post-operative stroke, thromboembolism, and
mortality, as highlighted in various reviews (79), but the
focus of this paper will be thromboprophylaxis in the
nonsurgical setting, and more on the outpatient nonacute
clinical setting.
Age and Risk of Stroke in Studies
The importance of age as a risk factor for stroke in AF
populations has been specifically evaluated in 17 studies
(Table 1) examining the independent risk associated with

828

Marinigh et al.
Age Is a Risk Factor for Stroke in Atrial Fibrillation

JACC Vol. 56, No. 11, 2010

September 7, 2010:82737

age, either as a continuous variable

(1,10 12) or incrementally by decade (1321), or by employing an
AF atrial fibrillation
arbitrary cutoff (e.g., 75 years)
CI confidence interval
(2225). Twelve studies found inHR hazard ratio
creasing age to have an independent
ICH intracranial
effect on the stroke risk (1,10,11,
hemorrhage
1317,2123,25), whereas 5 studies
INR international
failed to find such an association
normalized ratio
(12,18 20,24).
OAC oral anticoagulation
In a pooled analysis of 5 randomRCT randomized
ized controlled trials (AFASAK
controlled trial
[Copenhagen Atrial Fibrillation,
RR relative risk
Aspirin, and Anticoagulation],
TIA transient ischemic
SPAF [Stroke Prevention in Atrial
attack
Fibrillation Investigators trial],
TTR time in therapeutic
BAATAF [Boston Area Anticoagrange
ulation Trial For Atrial Fibrillation],
CAFA [Canadian Atrial Fibrillation Anticoagulation study], and SPINAF [Stroke Prevention In
Nonrheumatic Atrial Fibrillation]), the overall relative risk (RR) of
stroke associated with age (by increasing decade) was 1.4 (95%
confidence interval [CI]: 1.1 to 1.8) (13). Age also emerged as an
independent predictor of ischemic stroke in prospective cohort or
case-control studies (15,22,26 40) (Table 2).
Being age 65 years or older was associated with a 3-fold
increased risk of stroke (RR: 3.3, 95% CI: 1.92 to 5.81) in an
observational study (22), with the Framingham study demonstrating that age (per decade) was independently associated
with stroke, with a RR of 1.32 (95% CI: 1.02 to 1.76) (15).
Among the 4 studies that evaluated thresholds of age to define
age-related stroke risk (2225), only 1 (24) did not find that
being 70 years of age was a significant stroke risk factor. In
this study, as in AFASAK I (12), hypertensionwhich is a
Abbreviations
and Acronyms

well-known risk factor for strokealso failed to emerge as an

independent risk factor for stroke in AF (24).
Further, the recent van Walraven et al. meta-analysis of
randomized controlled trials (RCTs) (41) demonstrated that
age independently (adjusted for sex, year of randomization,
history of cerebrovascular disease, diabetes mellitus, hypertension, and congestive heart failure) increased the risk of ischemic
stroke (1.45, 95% CI: 1.26 to 1.66 per decade).
Therefore, the balance of evidence suggests that age is an
independent risk for stroke, with the magnitude of risk
varying dependent on whether an incremental risk per
decade or an age cutoff is employed (Table 2). There is a
steep increase in the lifetime incidence of stroke with age
both in men and women. The risk starts to rise at age 55 to
59 years from 5.9% in men and 3.0% in women to 11.0%
and 7.2%, respectively, in the next decade, reaching an
incidence of 22.3% and 23.9% in the 80- to 84-year-old
group (1). Studies that have dichotomized age suggest a
1.4-fold increased risk of stroke per decade (13).
Risk Stratification Schemes
The absolute risk of stroke varies widely among patients
with AF and is dependent not only on chronological age,
but also on existing comorbidities and other clinical features. Indeed, multiple stroke risk stratification schemes for
AF patients have been proposed (42) that vary substantially
in complexity and incorporate different combinations of
clinical and echocardiographic parameters. However, at the
core of all the existing and most frequently employed
schemes are 3 key features that have been independently and
consistently associated with stroke in AF patients: advancing
age (1,10 25), previous stroke or transient ischemic attack
(TIA) (13,1518,4348), and hypertension (13,16,17,4348).

Increasing
as a Risk
Factor
Table 1 Age
Increasing
Age
as a For
RiskStroke
Factor For Stroke
Study (Ref. #)

Age Criteria Employed

Risk (95% CI) Associated With Age

91

Age 75 yrs

Cabin et al., 1990 (24)

272

Age 70 yrs

Petersen et al., 1990 (12)

336

Correlation with increasing age

*
*

Flegel and Hanley, 1989 (25)

Wolf et al., 1991 (1)

5,070

Age 8090 yrs

Moulton et al., 1991 (22)

2,516

HR: 2.51 (1.145.51) 75 yrs

p Value
0.05
NS
NS
0.001

Age 75 yrs

OR: 1.76 (1.082.89)

0.05

568

Incremental risk per decade

RR: 1.2 (0.91.6)

0.20

1,593

Incremental risk per decade

RR: 1.4 (1.11.8) per decade

0.05

Van Latum et al., 1995 (18)

375

Incremental risk per decade

HR: 1.3 (0.53.0) 70 yrs

Yoshida et al., 1996 (11)

122

Correlation with increasing age

RR: 1.11 (1.041.19)

0.0052

SPAF Investigators, 1992 (19)

AFI, 1994 (13)

SPAF III, 1998 (14)

NS

829

Incremental risk per decade

RR: 1.7 (1.12.6) per decade

0.01

1,066

Incremental risk per decade

RR: 1.5 (1.11.9) per decade

0.008

Naghami et al., 1998 (20)

290

Incremental risk per decade

OR: 1.33 (1.041.71) per decade

Hart et al., 1999 (16)

460

Incremental risk per decade

RR: 2.0 per decade

0.001

Hart et al., 2000 (21)

2,010

0.001

AFI, 1998 (17)

Incremental risk per decade

RR: 2.1/1.7 per decade

Inoue et al., 2000 (23)

740

Age 65 yrs

RR: 3.33 (1.925.81)

Wang et al., 2003 (15)

705

Incremental risk per decade

Stollberger et al., 2004 (10)

409

Correlation with increasing age

*
RR: 1.06 (1.041.08)

*Not reported; intermittent AF/sustained AF; confidence intervals not reported.

AFI Atrial Fibrillation Investigators; HR hazard ratio; NS not significant (p 0.05); OR odds ratio; RR relative risk; SPAF Stroke Prevention in Atrial Fibrillation Study.

NS

0.0001
0.05
0.0006

JACC Vol. 56, No. 11, 2010

September 7, 2010:82737

Risk
of Stroke/Thromboembolism
and Major Bleeding
by Antithrombotic
Therapy in Randomized
Controlled Trials
and Cohort
Table
2 Risk of Stroke/Thromboembolism
and Major
Bleeding by Antithrombotic
Therapy in Randomized
Controlled
TrialsStudies
and Cohort Studies
Stroke Risk (%/yrs)
Study (Ref. #)

Study Design

Age, yrs
(Mean)

Warfarin

Aspirin Control/Pl (RR)

Major Hemorrhage (%/yrs)

Warfarin

Aspirin

Control/Pl

Mean
Follow-Up
(yrs)

Therapy

Randomized controlled trials

AFASAK I, 1989 (26)

BAATAF*, 1990 (27)

SPAF I, 1991 (28)

EAFT 1993 (29)

1,007 RCT
Warfarin/placebo
Aspirin/placebo

6.2
6.2

0.6
0.3

0.41

2.98

0.4
(2/212)

1,330 RCT
627 warfarin/aspirin/placebo
703 aspirin/placebo

2.3

1.5

3.6

7.4
6.3

1,007 RCT
71.1
669 warfarin/aspirin/placebo
338 aspirin/placebo

8.5
15.5

16.5
19.0

2.6
0.7

From 1.0% (65

yrs, no risk
factors) to
8.1% (75
yrs, 1 or more
risk factors)

1.3

1.0

1.7
4.2

0.9
1.6

420 RCT
212 warfarin
208 controls (46% aspirin)

1,238 Analysis of pooled data from

5 RCTs
1,889 pts-yrs warfarin/
1,802 control
1,132 pts-yrs aspirin/
1,133 placebo

SPAF II, 1994 (30)

1,100 RCT
715 aspirin/warfarin (age
75 yrs)
385 aspirin/warfarin (age
75 yrs)

Pengo et al., 1998 (32)

5.2
68

69

64
80

4.6
1.3
3.6

4.3
1.9
4.8

Warfarin INR 2.84.2

Aspirin 75 mg/day
0.2
(1/208 episode)

1.4

1.6
1.9

0.7
0.6

2.2

Warfarin INR 1.52.7

Controls: 46% on aspirin

1.3

Warfarin INR 2.04.5

Aspirin 325 mg/day

2.3

Warfarin INR 2.54.0

Aspirin 300 mg/day

1.0

Aspirin 75 to 325 mg/day

Warfarin INR 1.21.5 min,
2.84.2 max

2.7

Warfarin INR 2.04.5

Aspirin 325 mg/day

1,044 RCT (high risk)

Warfarin

1.9

2.1

Warfarin INR 2.03.0

Warfarin plus aspirin

7.9

2.4

Aspirin 325 mg plus warfarin

INR 1.52.1

303 RCT

74

1.2

153 warfarin INR 23

0/153

2.6

Warfarin INR 23

150 warfarin 1.25 mg/day

5/150 (3.6
vs. 6.2)

1.0

Warfarin (1.25 mg/day)

Continued on next page

Marinigh et al.
Age Is a Risk Factor for Stroke in Atrial Fibrillation

AFI, 1994 (13)

SPAF III, 1996 (31)

1.2
2.7

829

830

Continued
Stroke Risk (%/yrs)

Study (Ref. #)
AFASAK II, 1998 (33)

Study Design

677 RCT

Age, yrs
(Mean)

6,706 RCT (1 or more risk factors

for stroke)
3,371 warfarin
3,335 clopidogrel plus aspirin

WASPO, 2007 (53)

75 RCT

973 RCT

Warfarin

Aspirin

13/167
11/171
10/170
9/169
3.4

3/167
1/171
4/170
2.7#

1.4

2.02 (OAC at entry)

2.92 (no OAC at entry)

2.63 (OAC at entry)

1.73 (no OAC at entry)

1/39

1/36

3/39

1.0

TIA

(2 INR 4.5)

Aspirin 300 mg vs.

warfarin (INR 23)

3.8

1.4

1.6

2.7

Warfarin (INR 23) or

aspirin (75 mg)

1.28

Warfarin INR 23,

clopidogrel 75 mg plus
aspirin

2.39 (Cl)
82 median

1.8

1.28 (median) Warfarin (INR 23) vs.

clopidogrel (75 mg)
plus aspirin (75100 mg)

488 warfarin
485 aspirin
ACTIVE-W, 2008 (34)

6,706 RCT
CHADS2 1
Warfarin
Clopidogrel plus aspirin
CHADS2 1
Warfarin
Clopidogrel plus aspirin

Therapy

Warfarin 1.25 mg/day,

warfarin 1.25 mg/day plus
aspirin 300 mg/day,
aspirin 300 mg/day
warfarin INR 23

5/169

70.2

81.5

Control/Pl

Mean
Follow-Up
(yrs)
NA

36 warfarin
39 aspirin
BAFTA, 2007 (52)

Aspirin Control/Pl (RR)

74 median

167 1.25 mg/day warfarin

171 warfarin plus aspirin
170 warfarin (INR 23)
169 aspirin
ACTIVE W, 2006 (72)

Warfarin

Major Hemorrhage (%/yrs)

70.0
0.43
2.01

1.25 (Cl)
3.15 (Cl)

1.36
1.81

Marinigh et al.
Age Is a Risk Factor for Stroke in Atrial Fibrillation

Continued
Table 2

2.09 (Cl)
2.63 (Cl)

Continued on next page

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JACC Vol. 56, No. 11, 2010

September 7, 2010:82737

Continued
Table 2

Continued
Stroke Risk (%/yrs)

Study (Ref. #)

ACTIVE A, 2009 (35)

7,554

Yamaguchi, 2000 (36)

115

Study Design
RCT

Age, yrs
(Mean)

Warfarin

Aspirin

Major Hemorrhage (%/yrs)

Control/Pl (RR)

Warfarin

Aspirin

71

3.6

3,772 clopidogrel plus aspirin

Clopidogrel 2.4

Clopidogrel 2.0

3,782 aspirin

Placebo 3.3

Placebo 1.3

RCT

Control/Pl

Mean
Follow-Up
(yrs)

66.7

Therapy
(Unsuitable for warfarin)
Clopidogrel 75 mg vs.
placebo

1.82

55 warfarin (conventionalintensity INR 2.23.5)

1.1

6/55 (conventionalintensity INR)

60 warfarin (low-intensity
INR 1.52.1)

1.7

0/60 (low-intensity INR)

Observational cohort studies

SPAF III, 1998 (37)

892** Prospective cohort study

67

2.0

0.7

Aspirin 325 mg/day

Aspirin
ATRIA, 1999 (38)

13,559

Mixed retrospective and

prospective cohort study

73 median

1.27

2.10 (no
warfarin)

0.58

0.32 (no warfarin)

6 median

6,353 not on warfarin

Warfarin
No warfarin

7,206 on warfarin
2,012

van Walraven et al.,

4,052
2002 (57) (6 trials)

Longitudinal cohort study

460 intermittent
1,552 sustained

66
70
0.001

Meta-analysis

71.7

3.2
3.3
2.4

4.5

1,939 warfarin

2.2 (0.4 lethal bleeding) 1.3 (0.2 lethal

bleeding)

Aspirin 325 mg/day

Aspirin 325 mg/day plus
warfarin 1.25 mg/day

1.9

Aspirin 75325 mg
Warfarin INR 23

2,113 aspirin or aspirin plus

1.25 mg warfarin
Gage et al. (AFI, SPAF, 2,580
ACCP, CHADS2,
Framingham), 2004
(39)

Patients on aspirin or aspirin

plus low-dose warfarin

Ortiz et al., 2008 (40)

Retrospective observational

296

Analysis of pooled data

Aspirin 325 mg/day plus

warfarin 1.25 mg/day
72

4.2

not reported

1.9

Aspirin 75 and 325 mg/day,

aspirin plus warfarin 2 mg
median dose (INR 1.4)

data not reported

1.4

90% aspirin,
10% no therapy

2.5
(without
prior cerebral ischemia)
75

3.51

Continued on next page

Marinigh et al.
Age Is a Risk Factor for Stroke in Atrial Fibrillation

Hart et al.,
2000 (21)

831

832

Continued
Stroke Risk (%/yrs)

Study (Ref. #)
van Walraven et al.,
2009 (41)

Study Design

8,932 Pooled analysis of

patient-level data from
6 published, randomized
clinical trials.

Age, yrs
(Mean)

Warfarin

71.7

2.4

Aspirin Control/Pl (RR)

3.8

Major Hemorrhage (%/yrs)

Warfarin

Aspirin

2.2

1.2

Control/Pl

Mean
Follow-Up
(yrs)
2

1,939 aspirin

Therapy
Warfarin

Aspirin

2,113 warfarin
Poli et al., 2009 (75)

783 Prospective observational

study

75

Not reported

n 456 (80 yrs)

1.4

n 327 (80 yrs)

0.9

2.56

Warfarin (INR 23)

1.2

No warfarin

Marinigh et al.
Age Is a Risk Factor for Stroke in Atrial Fibrillation

Continued
Table 2

2.5
Gage et al. (CHADS2),
2001 (49)

Wang et al., 2003 (15)

1,733 Results from the National

Registry of Atrial
Fibrillation

705 Prospective, communitybased, observational

cohort

4.4

(increases
1.5-fold as
CHADS increases 1)
75

2.9

Warfarin/no warfarin

*Major bleeding: intracranial hemorrhage, fatal bleeding, bleeding leading to transfusion of 4 U of packed red blood cells within 48 h; INR is estimated; patients with a recent TIA or minor ischemic stroke. Primary events: death from vascular disease, nonfatal stroke,
nonfatal myocardial infarction, or systemic embolism; the 6 patients who had intracranial bleeding while taking warfarin had higher systolic and diastolic blood pressure at entry to the study; primary events: stroke, non-CNS systemic embolus; primary events: stroke,
non-CNS systemic embolus, intracranial hemorrhage, fatal hemorrhage, vascular death; #primary events: stroke, non-CNS systemic embolus, intracranial hemorrhage; **major bleeding was defined as any bleeding requiring transfusion of at least 2 U of red blood cells or
equivalent of whole blood, or which was severe. Severe bleeding was bleeding associated with any of the following: death, drop in hemoglobin of at least 50 g/l, substantial hypotension with the need for inotropic agents, intraocular bleeding leading to substantial loss of
vision, bleeding requiring surgical intervention (other than vascular site repair), symptomatic intracranial hemorrhage, or requirement for a transfusion of at least 4 U of blood. Minor bleeding was any other bleeding requiring modification of the study drug regimen; not
reported; the stroke rates rose with increasing CHADS; during follow-up, 147 patients became age 80 years.
ACCP American College of Chest Physicians; ACTIVE A Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events-Aspirin-Clopidogrel; ACTIVE W Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular EventsWarfarin;
AFASAK Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation; AFI Atrial Fibrillation Investigators; ATRIA AnTicoagulation and Risk factors In Atrial Fibrillation; BAATAF the Boston Area Anticoagulation Trial For Atrial Fibrillation investigators; BAFTA
Birmingham Atrial Fibrillation Treatment of the Aged Study; CHADS2 congestive heart failure/hypertension/age/diabetes/prior stroke; Cl clopidogrel; CNS central nervous system; EAFT European Atrial Fibrillation Trial; INR international normalized ratio; NA
not available; PATAF Primary prevention of Arterial Thromboembolism in nonrheumatic Atrial Fibrillation; OAC oral anticoagulation; Pl placebo; SPAF Stroke Prevention in Atrial Fibrillation Study; WASPO Warfarin versus Aspirin for Stroke Prevention in
Octogenarians with atrial fibrillation.

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Other predictors of stroke among AF patients include diabetes

(13,1517,44 48), heart failure (43 47,49), left ventricular
systolic dysfunction (17,43 47), systolic blood pressure
(15,16,18,43,46,48), and coronary artery disease (44,46,48).
Female sex is also emerging as a recognized, independent risk
factor for stroke and thromboembolism (15,16,43,49,50).
Among trial-derived age cutoffs, age 75 years is the
most widely used. Age 75 years is considered a high-risk
factor for stroke in AF patients in the AF Investigators
analysis (17) and in the American College of Chest Physicians guidelines (44,45). In the SPAF trial, age 75 years
was also considered a high-risk factor for stroke in women
and hypertensive patients (16). According to the American
College of Cardiology (ACC)/American Heart Association
(AHA)/European Society of Cardiology (ESC) Guidelines
2006 (47) and the CHADS2 (congestive heart failure/
hypertension/age/diabetes/prior stroke) score (49), age 75
years is an independent risk factor for stroke, whereas the
NICE (National Institute for Health and Clinical Excellence) guidelines consider age 75 years as a high-risk
factor for stroke in patients with diabetes, vascular disease,
or hypertension (46).
However, the risk of AF increases as age rises since age is
not a yes/no phenomenon (above or below a threshold). The
stroke risk associated with AF increases dramatically from
the age of 65 years onwards (3,4,22). For example, being age
72 years with 1 risk factor for stroke does not mean that
your risk of stroke is appreciably less than that of a
75-year-old with 1 risk factor (except when working out
stroke risk using risk stratification schemes). Indeed, the
ACC/AHA/ESC 2006 guidelines (47) highlighted age 65
to 74 years as a less validated or weaker risk factor for
stroke.
A refined version of the original CHADS2 score and
NICE schema, incorporating these less well-validated or
weaker stroke risk factors, female sex, age 65 to 74 years,
and vascular disease, and known as CHA2DS2-VASc score
(51), was recently validated in the Euro Heart Survey on AF
cohort. This refined stroke risk stratification system classifies all patients age 75 years and older as high risk. This is
justified in part by the van Walraven et al. meta-analysis of
RCTs (41), as well as the BAFTA (Birmingham Atrial
Fibrillation Treatment of the Aged) (52) and WASPO
(Warfarin versus Aspirin for Stroke Prevention in Octogenarians with atrial fibrillation) (53) trials. Indeed, the cohort
analysis by Gorin et al. (54) which shows that of the
individual risk factors in an AF patient with a CHADS2
score of 1, age 75 years carries the highest stroke risk,
compared with heart failure, diabetes, or hypertension.
Further, CHA2DS2-VASc also places greater emphasis on
being age 65 to 74 years, with patients in this age category
scoring 1 point for this risk factor alone (51).
The new CHA2DS2-VASc score (51) has sought to
simplify the approach to anticoagulation in AF patients,
suggesting oral anticoagulation (whether with warfarin or
the new oral anticoagulants that avoid the disadvantages of

Marinigh et al.
Age Is a Risk Factor for Stroke in Atrial Fibrillation

833

warfarin, such as dabigatranif approved) in moderatehigh risk AF patients (i.e., a CHA2DS2-VASc score of 1),
whereas those who are truly low-risk subjects (i.e.,
CHA2DS2-VASc score 0), who could even be managed
with no antithrombotic therapy (Table 3).
Antithrombotic Treatment
and Stroke Risk in Elderly AF Patients
Even when there is evidence that age and AF independently
increase stroke risk, elderly people with AF are less likely to
receive oral anticoagulant therapy (OAC) despite standing
to receive the greatest benefit from such treatment (55).
Before the BAFTA trial (52), older patients (75 years)
were significantly under-represented in RCTs of OAC
versus placebo (mean age 69 years) (56) or antiplatelet
therapy (mean [SD] age: 71.7 [8.8] years) (57), and therefore, the evidence base for the value of OAC in the elderly
population was not known. The individual meta-analysis by
van Walraven et al. (57) (conducted prior to the publication
of BAFTA) suggested that OAC compared with aspirin
reduced stroke (2.4 vs. 4.5 events per 100 patient-years;
hazard ratio [HR]: 0.55; 95% CI: 0.43 to 0.71), but resulted
in a 2-fold increase in bleeding risk.
However, the BAFTA trial (52) demonstrated that warfarin significantly reduces stroke risk in the elderly (mean
[SD] age: 81.5 [4.2] years) compared with aspirin (1.8% vs.
3.8%, respectively; RR: 0.48, 95% CI: 0.28 to 0.80; p
0.003). Another small RCT, of WASPO (53), also provides
support for the use of warfarin over aspirin to reduce adverse
events (composite end point of thromboembolism, major
bleeding, and death) in elderly AF patients (80 years of
age).
The van Walraven et al. (57) meta-analysis based on data
from 6 RCTs (mean age 71.7 years), also showed that OAC
significantly decreases the risk of ischemic strokes (2.4%/yrs
vs. 4.5%/yrs; HR: 0.55; 95% CI: 0.43 to 0.71) compared
with aspirin for AF patients. More recently, these results
have been confirmed by an updated meta-analysis of 11
Stroke
Assessment
in AF: CHA2DS
-VASc*
Table Risk
3
Stroke
Risk Assessment
in 2AF:
CHA2DS2-VASc*
Stroke Risk Factors

Score

Congestive heart failure/LV dysfunction

Hypertension

Age 75 yrs

Diabetes mellitus

Stroke/TIA/TE

Vascular disease (prior MI, PAD, or aortic plaque)

Age 6574 years

Sex category (i.e., female sex)

The CHA2DS2-VASc schema assesses stroke risk in patients with nonvalvular atrial fibrillation (51).
*For a CHA2DS2-VASc score 1, such patients are high risk and should have oral anticoagulation
(e.g., warfarin); For a CHA2DS2-VASc score 1, antithrombotic therapy is recommended, either as
oral anticoagulation or aspirin 75 to 325 mg daily, but oral anticoagulation is preferred rather than
aspirin; For a CHA2DS2-VASc score 0 (truly low risk), either aspirin 75 to 325 mg daily or no
antithrombotic therapy can be used, but no antithrombotic therapy may be preferred. Maximum
score is 9 (51).
TE thromboembolic event; TIA transient ischemic attack.

834

Marinigh et al.
Age Is a Risk Factor for Stroke in Atrial Fibrillation

RCTs, including BAFTA, which also demonstrated that

OAC significantly reduced the risk of ischemic stroke
compared with aspirin and placebo (OAC adjusted HR per
decade increase: 0.36; 95% CI: 0.29 to 0.45; antiplatelets:
0.81; 95% CI: 0.72 to 0.90) (41). In this analysis, the relative
benefit of OAC in preventing stroke was not significantly
affected by increasing age, whereas the benefit of aspirin
decreased significantly as patients aged. The recent study by
Singer et al. (58) from the ATRIA (AnTicoagulation and
Risk Factors in Atrial Fibrillation) cohort also showed a
reduction in absolute stroke risk with warfarin: the benefit
was greater in very elderly patients (age 85 years) and
among those at high stroke risk.

Antithrombotic Treatment and

Bleeding Risk in Elderly AF Patients
Physicians may be apprehensive about prescribing OAC to
elderly patients, given concerns about a higher risk of
OAC-associated hemorrhage (13,17,44,52,59,60) among
older people. Intracranial hemorrhage (ICH) is the most
feared and devastating complication of warfarin therapy
(61). The risk of ICH is increased 2.5-fold among people
age 85 years (61), although the absolute risk of warfarinassociated ICH in AF patients is relatively low at 0.2% per
year (62). A recent meta-analysis of RCTs, including
BAFTA, demonstrated that increasing age raises the risk of
serious bleeding (HR: 1.61; 95% CI: 1.47 to 1.77) (41),
although the risk of major hemorrhage was similar among
patients receiving warfarin and aspirin (1.4% vs. 1.6%; RR:
0.87, 95% CI: 0.43 to 1.73).
Of the published bleeding risk stratification schema
available, all include age as a risk factor for bleeding
(63,64), but there is no consistency in the other risk
factors included in these bleeding risk models. The most
recently proposed risk schema is the HAS-BLED (HASBLED: Hypertension, Abnormal renal/liver function,
Stroke, Bleeding history or predisposition, Labile INR,
Elderly [65], Drugs/alcohol concomitantly) score (65)
(Table 4), which could be used as a simple, easy assessment
of bleeding risk in AF patients: thus, a score of 3 indicates
high risk, and some caution and regular review of the patient
is needed, following the initiation of antithrombotic therapy, whether with a vitamin K antagonist or aspirin.
The mechanism by which age is associated with major
hemorrhage may be multifactorial (66,67) and can be
broadly divided into treatment- and person-dependent reasons. High anticoagulation intensity and INR variability are
risk factors for hemorrhage, with INR 3.5 associated with
an almost 5-fold increased risk of major hemorrhage,
especially among the elderly (age 80 years) (61,68).
Often, lower-intensity INR ranges are employed among
elderly patients to prevent warfarin-associated hemorrhages.
However, an INR 2.0 is not associated with a lower rate
of ICH than standard INR targets (2.0 to 3.0) in the elderly

JACC Vol. 56, No. 11, 2010

September 7, 2010:82737

HAS-BLEDRisk
Bleeding
Bleeding
Assessment
Risk
in AF:
Bleeding
RiskScore
Assessment
in AF:
Table 4
HAS-BLED Bleeding Risk Score
Letter

Clinical Characteristic*

Hypertension

Abnormal renal and liver function (1 point each)

Points Awarded
1
1 or 2

Stroke

Bleeding

Labile INRs

Elderly

Drugs or alcohol (1 point each)

1
1 or 2
Maximum 9 points

*Hypertension is defined as systolic blood pressure 160 mm Hg. Abnormal kidney function is
defined as the presence of chronic dialysis or renal transplantation or serum creatinine 200
mol/l. Abnormal liver function is defined as chronic hepatic disease (e.g., cirrhosis) or biochemical evidence of significant hepatic derangement (e.g., bilirubin 2 upper limit of normal, in
association with AST/ALT/ALP (aspartate aminotransferase/alanine aminotransferase/alkaline
phosphatase) 3 upper limit normal, and so on). Bleeding refers to previous bleeding history
and/or predisposition to bleeding (e.g., bleeding diathesis, anemia). LabileINRs (international
normalized ratios) refers to unstable/high INRs or poor time in therapeutic range (e.g., 60%).
Drugs/alcohol use refers to concomitant use of drugs, such as antiplatelet agents, nonsteroidal
anti-inflammatory drugs (65).

(61,69) and should be avoided given the obvious associated

increased risk of thromboembolic events at suboptimal INR
levels (70). The risk of hemorrhagic events is also higher
during the first 90 days of treatment, decreasing considerably thereafter (71), and the hazards related to warfarin
seem to be greater in patients new to warfarin compared
with warfarin-established patients before study entry (72).
Crucial to both bleeding and stroke rates is the quality of
INR control, which is contingent on the level of INR
surveillance and provision of OAC services. Recent studies
have demonstrated that time in therapeutic range (TTR)
needs to be at a minimum of 58% to derive benefit from
OAC in an analysis from ACTIVE-W (Atrial Fibrillation
Clopidogrel Trial With Irbesartan for Prevention of Vascular Events) (73) and 71% outside of the trial setting
(74). In real-life clinical practice, beneficial levels of TTR
may be difficult to achieve. In a prospective observational
study of 783 AF patients (median age 75 years, range 37 to
94 years), patients had a TTR of 71% (75), with no
difference in TTR between patients age 80 and 80 years.
Although being age 80 years was associated with a 2-fold
increased risk of bleeding (75), the absolute rate of major
bleeding of patients age 80 years is relatively low (rate: 2.5
%/yrs).
Other risk factors for major hemorrhage among AF
patients have been identified, including prior stroke and
gastrointestinal bleeding, hypertension, concomitant antiplatelet use, anemia, renal insufficiency, presence of cerebrovascular disease, and malignancy, all of which may be
more common among elderly people (63,64). Polypharmacy
(with the possibility of interacting drugs) and insufficient
education about anticoagulation also have been linked to
hemorrhage (71). In addition, cognitive dysfunction, functional impairments, and increased fall risk, further complicate OAC management in elderly patients (13).

JACC Vol. 56, No. 11, 2010

September 7, 2010:82737

Net Clinical Benefit

When prescribing OAC therapy for AF patients, we must
consider the net clinical benefit of such treatment. Two
recent analyses have addressed this issue. In an analysis of
the ATRIA cohort (58), the adjusted net clinical benefit of
warfarin (annualized rate of thromboembolic events minus
the annualized ICH rate [weighted]) for the overall cohort
was 0.68% per year (95% CI: 0.34% to 0.87%). The benefit
from anticoagulation was greater for those age 85 years or
older (2.34% per year [95% CI: 1.29% to 3.30%]) and for
patients with a history of ischemic stroke (2.48% per year
[95% CI: 0.75% to 4.22%]). Importantly, the TTR in the
ATRIA cohort was good at 65% (54).
The van Walraven et al. (41) meta-analysis of 11 RCTs
demonstrated an age-related increase in both ischemic
stroke and major bleeding risk, with OAC and antiplatelet
therapy significantly reducing the stroke risk (RR: 0.36; 95%
CI: 0.29 to 0.45, and 0.81; 95% CI: 0.75 to 0.88, respectively), with OAC increasing the risk of serious bleeding
(RR: 1.56; 95% CI: 1.03 to 2.37) compared with placebo
(41). There was an interaction between patient age and
stroke prevention. Antiplatelet therapy offered no additional
benefit in octogenarians over placebo. However, OAC
therapy continued to offer significant protection against
stroke with increasing age, although the benefit was attenuated. There was no interaction between age and OAC or
antiplatelet therapy for serious bleeding. Therefore, elderly
AF patients will receive a greater net clinical benefit from
OAC therapy as they face the greatest stroke risk. The
results of this meta-analysis (41) differ from their earlier
meta-analysis (57), which suggested that the relative benefit
of OAC over antiplatelet drugs may decrease as patients
age. The discrepancy in these findings may result from the
inclusion of 5 additional studies, increasing the number of
ischemic stroke events, raising the number of elderly patients (n 1,359, age 75 years), and employing age as a
continuous variable in the most recent statistical analyses
(41) compared with the dichotomization of a continuous
variable, comparing age 75 and 75 years (57).
New Oral Antithrombotic Medications
Although the advent of newer oral antithrombotic agents on
the horizon will hopefully offer greater therapeutic choice
for stroke prophylaxis in AF patients, with a more stable
pharmacokinetic profile and fewer inherent problems than
warfarin, there will still remain the need to evaluate net
clinical benefit.
The RE-LY (76) (Randomized Evaluation of Long
Term Anticoagulant Therapy) study recently demonstrated
that the oral direct thrombin inhibitor, dabigatran 110 mg
twice daily was associated with rates of stroke and systemic
embolism similar to those on warfarin (RR: 0.91; 95%
CI: 0.74 to 1.11; p 0.34) but with significantly lower
rates of major hemorrhage (3.36% vs. 2.71% per year) (RR

Marinigh et al.
Age Is a Risk Factor for Stroke in Atrial Fibrillation

835

with dabigatran: 0.80; 95% CI: 0.69 to 0.93; p 0.003).

Dabigatran 150 mg twice daily was superior to warfarin in
reducing rates of stroke and systemic embolism (RR with
dabigatran: 0.66; 95% CI: 0.53 to 0.82; p 0.001) but
demonstrated similar rates of major hemorrhage to the
warfarin group (3.36% vs. 3.11% per year; RR with dabigatran: 0.93; 95% CI: 0.81 to 1.07; p 0.31) (76).
Although these data are extremely encouraging, more
data on long-term safety are awaited, given there was an
increased risk of dyspepsia, gastrointestinal major hemorrhage, and myocardial infarction with dabigatran compared
with warfarin. Other data from another class of novel oral
anticoagulants, the oral factor Xa inhibitors, are awaited.
Conclusions
Physicians may be apprehensive about prescribing OAC to
elderly patients, given concerns about a higher risk of
OAC-associated hemorrhage (63,68,7,75). However, age
alone should not prevent prescription of OAC in elderly
patients, given the potential greater net clinical benefit
among such patients (41,58). Appropriate stroke and bleeding risk stratification and choice of antithrombotic therapy
are essential. Once OAC is initiated, good INR control (at
least 65% TTR) and the provision of a health care infrastructure to support such INR therapeutic targets are crucial
to prevent warfarin-associated complications.
Reprint requests and correspondence: Dr. Deirdre A. Lane, City
Hospital, University of Birmingham Centre for Cardiovascular
Sciences, Dudley Road, Birmingham, West Midlands B18 7QH,
United Kingdom. E-mail: deirdre.lane@swbh.nhs.uk.

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Key Words: atrial fibrillation y bleeding risk y elderly y net clinical
benefit y stroke risk y warfarin.