ORIGINAL CONTRIBUTION
Aspirin for Prevention of Cardiovascular
Events in a General Population Screened
for a Low Ankle Brachial Index
A Randomized Controlled Trial
F. Gerald R. Fowkes, FRCPE
Jacqueline F. Price, MD
Marlene C. W. Stewart, PhD
Isabella Butcher, PhD
Gillian C. Leng, MD
Alistair C. H. Pell, MD
Peter A. G. Sandercock, DM
Keith A. A. Fox, FRCP
Gordon D. O. Lowe, DSc
Gordon D. Murray, PhD
for the Aspirin for Asymptomatic
Atherosclerosis Trialists
T
HE ANKLE BRACHIAL INDEX
(ABI), which is the ratio of sys-
tolic pressure at the ankle to the
arm, is used in the diagnosis of
peripheral artery disease affecting the
legs. Also, a low ABI is associated with
concomitant coronary and cerebrovas-
cular disease1 and, in healthy individu-
als, with an increased risk of future vas-
cular events, independently of
cardiovascular risk factors.2 In a meta-
analysis of 16 cohort studies of healthy
individuals, the 10-year risk of a ma-
jor coronary event in men with an ABI
of 0.90 or less was 27% compared with
9% in those with an ABI in the normal
range of 1.11 to 1.40.2 Respective fig-
ures for women were 19% and 6%.
For editorial comment see p 880.
CME available online at
www.jamaarchivescme.com
and questions on p 892.
©2010 American Medical Association. All rights reserved.
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CLINICIAN’S CORNER
Context A low ankle brachial index (ABI) indicates atherosclerosis and an increased
risk of cardiovascular and cerebrovascular events. Screening for a low ABI can identify
an asymptomatic higher risk group potentially amenable to preventive treatments.
Objective To determine the effectiveness of aspirin in preventing events in people
with a low ABI identified on screening the general population.
Design, Setting, and Participants The Aspirin for Asymptomatic Atherosclerosis
trial was an intention-to-treat double-blind randomized controlled trial conducted from
April 1998 to October 2008, involving 28 980 men and women aged 50 to 75 years
living in central Scotland, free of clinical cardiovascular disease, recruited from a com-
munity health registry, and had an ABI screening test. Of those, 3350 with a low ABI
(ⱕ0.95) were entered into the trial, which was powered to detect a 25% proportional
risk reduction in events.
Interventions Once daily 100 mg aspirin (enteric coated) or placebo.
Main Outcome Measures The primary end point was a composite of initial fatal or
nonfatal coronary event or stroke or revascularization. Two secondary end points were
(1) all initial vascular events defined as a composite of a primary end point event or an-
gina, intermittent claudication, or transient ischemic attack; and (2) all-cause mortality.
Results After a mean (SD) follow-up of 8.2 (1.6) years, 357 participants had a primary
end point event (13.5 per 1000 person-years, 95% confidence interval [CI], 12.2-15.0).
No statistically significant difference was found between groups (13.7 events per 1000
person-years in the aspirin group vs 13.3 in the placebo group; hazard ratio [HR], 1.03;
95% CI, 0.84-1.27). A vascular event comprising the secondary end point occurred in 578
participants (22.8 per 1000 person-years; 95% CI, 21.0-24.8) and no statistically signifi-
cant difference between groups (22.8 events per 1000 person-years in the aspirin group
vs 22.9 in the placebo group; HR, 1.00; 95% CI, 0.85-1.17). There was no significant dif-
ference in all-cause mortality between groups (176 vs 186 deaths, respectively; HR, 0.95;
95% CI, 0.77-1.16). An initial event of major hemorrhage requiring admission to hos-
pital occurred in 34 participants (2.5 per 1000 person-years) in the aspirin group and 20
(1.5 per 1000 person-years) in the placebo group (HR, 1.71; 95% CI, 0.99-2.97).
Conclusion Among participants without clinical cardiovascular disease, identified with
a low ABI based on screening a general population, the administration of aspirin com-
pared with placebo did not result in a significant reduction in vascular events.
Trial Registration isrctn.org Identifier: ISRCTN66587262
JAMA. 2010;303(9):841-848 www.jama.com
Author Affiliations: Centre for Population Health Sciences Monklands Hospital, Lanarkshire, Scotland (Dr Pell); and
(Drs Fowkes, Price, Stewart, Butcher, and Murray), Cen- Division of Cardiovascular and Medical Sciences, Univer-
tre for Cardiovascular Science (Dr Fox), and Centre for sity of Glasgow, Glasgow, Scotland (Dr Lowe).
Clinical Brain Sciences (Dr Sandercock), University of Ed- Corresponding Author: F. Gerald R. Fowkes, FRCPE,
inburgh,Scotland;DepartmentofPublicHealthandPolicy, Wolfson Unit for Prevention of Peripheral Vascular Dis-
London School of Hygiene and Tropical Medicine, Lon- eases, University of Edinburgh, Teviot Place, Edin-
don, England (Dr Leng); Department of Cardiology, burgh EH8 9AG (gerry.fowkes@ed.ac.uk).
(Reprinted) JAMA, March 3, 2010—Vol 303, No. 9 841
 ASPIRIN AND PREVENTION IN LOW ANKLE BRACHIAL INDEX
Because the ABI is a simple, inex-
pensive, noninvasive test, it could be
used in population screening pro-
grams to identify a novel subgroup
potentially amenable to preventive
treatments. This is of particular
importance given that current pri-
mary prevention strategies in the
general population are of limited
benefit. 3,4 Guideline development
groups have suggested that ABI
screening be considered in primary
care or in the community, especially
among certain high-risk groups, 5,6
whereas others do not recommend
screening.7
Although an ABI might better de-
fine risk, a major argument against
screening is lack of evidence for an ef-
fective intervention for those with a low
ABI.7 Antiplatelet drugs, including as-
pirin, are effective in the secondary pre-
vention of events of patients with
known vascular disease,8 but aspirin
may have only a modest effect as a pri-
mary prevention for healthy individu-
als.9 We aimed to determine whether
screening the general population for a
low ABI could identify a higher-risk
group who might derive substantial
benefit from aspirin therapy.
METHODS
Study Design
The Aspirin for Asymptomatic Athero-
sclerosis trial, conducted from April
1998 to October 2008, was a prag-
matic intention-to-treat, double-
blind, randomized controlled trial of
once daily low-dose aspirin (100 mg)
vs placebo involving individuals free of
clinical cardiovascular disease and with
a low ABI.
Ethical approval was granted by the
UK National Health Service research
ethics committees in Lanarkshire,
Greater Glasgow, and Lothian health
boards. All participants gave written in-
formed consent.
Study Population
The study population comprised men
and women aged 50 to 75 years at
baseline with no history of vascular
disease. Between April 1998 and
842 JAMA, March 3, 2010—Vol 303, No. 9 (Reprinted)
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December 2001 volunteers were
recruited from Lanarkshire, Glasgow,
and Edinburgh in central Scotland by
mailing individuals on Community
Health Indexes that contain the age
and sex of patients listed on the regis-
ters of general practitioners, 83% of
whom agreed that their patients could
be invited for screening. The study
was advertised in newspapers and on
fliers posted in general practice offices
and announced that only those who
had not had a heart attack or stroke or
who were not taking aspirin or warfa-
rin could participate in the screening.
Those wishing to take part were
invited to a local center for ABI
screening administered by specially
trained nurses.
Interventions
At screening clinics, participants lay
rested supinely for 5 minutes and
right and left brachial, posterior tibial,
and dorsalis pedis systolic pressures
were measured using a sphygmoma-
nometer and Doppler probe. The ABI
was calculated as ratio of the lowest
ankle pressure (lower of posterior
tibial and dorsalis pedis and of left
and right) to the higher pressure of
either arm. Those with an ABI of 0.95
or lower were entered into the trial
unless they had a history of myocar-
dial infarction, stroke, angina, or
peripheral artery disease; currently
used aspirin, other antiplatelet or
anticoagulant agents; had severe indi-
gestion; had chronic liver or kidney
disease; were receiving chemotherapy;
had contraindications to aspirin; and
had an abnormally high or low
hematocrit value (measured after the
screening). Baseline assessment for
trial participants included medical
history, medication, smoking status,
blood pressure, serum total choles-
terol levels, and socioeconomic sta-
tus.10 Quality control was maintained
by holding regular training days for
staff members.
Participants were randomized to
receive 100 mg of enteric-coated aspi-
rin daily or placebo. Consecutive par-
ticipant study numbers were assigned
©2010 American Medical Association. All rights reserved.
to aspirin or placebo with permuted
blocks of size 8, which varied ran-
domly. A staff member not involved
in the study produced the computer-
generated randomization list. Staff at a
single pharmacy prepared the bottles
containing aspirin or placebo and
labeled them with study numbers.
The trial recruits were allocated the
next available study number and
given the appropriately labeled bottle
containing a year’s supply of tablets.
Randomization lists in sealed enve-
lopes were available only to the phar-
macy, an independent member of staff
responsible for unblinding due to
clinical necessity, and an independent
statistician providing reports to the
data monitoring committee.
Follow-up
Participants were followed up after 3
months, 1 year, and 5 years at special
clinics and annually by telephone. They
received a midyear letter enquiring gen-
erally about problems and an end-of-
year newsletter. Participants kept a di-
ary of adherence. A specially trained
nurse assessed self-reported adher-
ence annually and mailed a new sup-
ply of tablets. If participants stopped the
drug for a nonmedical reason, they were
encouraged to restart. If they started
long-term antiplatelet medication due
to a vascular event or for another rea-
son, the study drug was discontinued.
Participants were followed up until the
end of the trial, irrespective of their ex-
periencing an end point or adverse
event.
Ascertainment of possible events
was sought annually from participant
follow-up, a study reply card attached
to general practitioner notes, flagging
for death at the NHS Central Registry,
and linkage to databases of deaths and
hospital discharges at NHS National
Services Scotland. Confirmation of
events was sought by review of hospi-
tal, general practitioner records, or
both independently by 2 members of
the outcome events committee with
adjudication by the full committee in
cases of disagreement. Vascular events
were classified using modified Ameri-
 ASPIRIN AND PREVENTION IN LOW ANKLE BRACHIAL INDEX

can Heart Association criteria 1 1

Figure 1. Study Flow Diagram
(eAppendix available at http://www
.jama.com). Confirmation of an 165 795 Individuals invited for ankle
adverse event required diagnosis by a brachial index screening

physician and adherence to predefined

criteria. 136 815 Excluded for having vascular disease or were
taking medication, refusing participation, or
unable to participate
End Points
The primary end point was a compos- 28 980 Underwent screening

ite of initial (earliest) fatal or nonfatal

24 066 Had ankle brachial index >0.95
coronary event or stroke or revascular-
ization. Two secondary end points were 4914 Considered for randomization
(1) all initial vascular events, defined
as a composite of a primary end point 1564 Excluded
event or angina, intermittent claudica- 923 Declined participation
259 Had contraindications for aspirin
tion or transient ischemic attack; and 96 Were taking exclusion medication
81 Had cardiovascular or other chronic disease
(2) all-cause mortality. 205 Excluded for other reasons

Statistical Analysis 3350 Randomized

The trial was powered to detect a 25%
proportional risk reduction in major 1675 Randomized to receive aspirin 1675 Randomized to receive placebo
vascular events. The predicted risk
reduction was based on evidence 5 Lost to follow-up 5 Lost to follow-up

that (1) event rates in asymptomatic

participants with a low ABI were simi-
lar to those with symptomatic periph-
eral artery disease,12-14 suggesting that
the risk reduction might be compa-
rable with patients who have clinical
disease (approximately 25% 15 ) and
(2) in stable angina, unlike acute
coronary syndromes with thrombosis
complicating atherosclerotic plaque,
the risk reduction could reach 33%.15
Previous trials had included effects of
nonadherence to treatment and of
concomitant aspirin use. Adjustment
was therefore not made for these
effects. The power calculation was
based on comparison of proportions
whereas the planned survival analysis
would be more sensitive. A sample
size of 3350 gave 80% power at 5%
significance (2 sided) to detect a
reduction in event rate from 12% to
9%. The 12% rate in the placebo
group was based on data from the
Edinburgh Artery Study, a cohort
with a similar population to our
trial.13 The sample size required ascer-
tainment of 350 events (200 placebo;
150 aspirin).
During the trial, the event rate was
60% of that predicted, consistent with
a decrease in the number of events in
©2010 American Medical Association. All rights reserved.
1675 Included in the primary analysis
Scotland over the same period. There-
fore, extended follow-up was planned
for another 4.5 years. Subsequently, on
advice from the data monitoring com-
mittee, the trial was stopped 14 months
early due to the improbability of find-
ing a difference in the primary end point
by the end date and an increase in ma-
jor bleeding (P ⬍ .05) in the aspirin
group. Despite stopping the trial early,
the required number of events was
achieved.
Study data were collected on stan-
dard forms, checked for complete-
ness, and double keyed into an Access
database. Analyses were by intention to
treat, with 2-tailed tests of signifi-
cance, and were performed using SAS/
STAT software, version 9.1 SAS Sys-
tem for Windows (SAS Institute Inc,
Cary, North Carolina) and SPSS for
Windows release 14.0.0 (SPSS, Chi-
cago, Illinois).
Kaplan-Meier plots of time from
enrollment to composite primary and
secondary end point events for the 2
treatment groups were produced.
Incidence rates per 1000 person-years
1675 Included in the primary analysis
(95% confidence intervals [CIs]) were
based on numbers of events and sur-
vival analysis follow-up times. Treat-
ment efficacy was assessed using uni-
variate Cox proportional hazards
regression model (only treatment in
the model).
Robustness of the result for the pri-
mary end point was assessed in a
multivariate Cox proportional hazards
regression model controlling for
baseline characteristics of age, ABI,
cholesterol levels, and systolic pres-
sure as continuous variables, with sex,
smoking status (current/previous/
never), and quintile of socioeconomic
status10 as categorical variables. All
covariates were complete except for
cholesterol, for which 20 missing
values were imputed using linear
regression.
Additional analyses were carried
out on predefined subgroups across
risk strata: male vs female and above
or below the median age of 62 years;
and post hoc for ABI cut points of
0.80, 0.85, 0.90; and excluding diabe-
tes. Cox proportional hazards regres-
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 ASPIRIN AND PREVENTION IN LOW ANKLE BRACHIAL INDEX

sion was used. A similar comparison sored because they either emigrated or Effectiveness End Points
was made between participants taking could not be contacted. A primary end point event occurred in
or not taking treatment as previously Baseline characteristics were simi- 357 participants (13.5 per 1000 person-
defined16 at 5 years of follow-up. lar in the aspirin and placebo groups years, 95% CI, 12.2-15.0). FIGURE 2
(T A B L E 1): 72% of participants shows that no statistically significant
RESULTS were women; 27% were in the most difference was found in event rates over
Participants deprived socioeconomic category; time between the groups (aspirin, 13.7;
Invitations to ABI screening were sent mean (SD) ABI was 0.86 (0.09); 95% CI, 11.8-15.9 vs placebo, 13.3; 95%
to 165 795 people aged 50 to 75 years mean (SD) serum cholesterol 238.5 CI, 11.4-15.4, events per 1000 person-
of whom 28 980 were screened (re- (41.9) mg/dL (to convert cholesterol years; HR, 1.03; 95% CI, 0.84-1.27). No
sponse rate 15.9% men, 18.9% wom- from mg/dL to mmol/L, multiply by statistically significant differences were
en). Those screened had similar distri- 0.0259); 33% were current smokers; found in individual primary end point
butions of age, sex, and socioeconomic and 3% reported that they had diabe- events between the groups (TABLE 2).
status to the target population.17 Of tes mellitus. Lipid-lowering therapy The secondary end point of all vas-
those screened, 4914 (17%) had a low use (including statins) was reported cular events occurred in 578 partici-
ABI (ⱕ0.95), 641 of whom met the ex- by 4% at baseline, increasing to 25% pants (22.8 per 1000 person-years, 95%
clusion criteria and 923 declined to par- at 5 years (26.0% aspirin group; CI, 21.0-24.8). The occurrence of these
ticipate in the trial. The remaining 3350 23.9% placebo group). Physician- or events did not differ over time be-
were randomly assigned to the aspirin self-prescribed aspirin at 5 years was tween groups (aspirin, 22.8; 95% CI,
(n=1675) or placebo (n=1675) groups reported by 16.4% in the aspirin 20.2-25.6 vs placebo, 22.9; 95% CI,
(F IGURE 1). Participants were fol- group and by 15.0% in the placebo 20.3-25.7 events per 1000 person-
lowed up for a mean (SD) of 8.2 (1.6) group, including those who had had years; HR, 1.00; 95% CI, 0.85-1.17;
years. Ten participants (0.3%) were cen- a cardiovascular event. eFigure [available at http://www.jama
.com]). Table 2 shows that there was
no evidence suggesting an effect of as-
Table 1. Characteristics of Participants in Aspirin and Placebo Groups at Randomization a pirin on angina, intermittent claudica-
Aspirin Group Placebo Group tion, or transient ischemic attack.
(n = 1675) (n = 1675)
All-cause mortality did not differ sig-
Age, mean (SD), y 62.2 (6.7) 61.7 (6.6)
nificantly between the aspirin group,
Men, No. (%) 481 (29) 473 (28)
176 deaths (12.8; 95% CI, 11.0-14.8 per
Socioeconomic status, No. (%) b
1 (most deprived) 438 (26) 450 (27) 1000 person-years) and the placebo
2 380 (23) 371 (22) group, 186 deaths (13.5; 95% CI, 11.6-
3 255 (15) 250 (15) 15.6 per 1000 person-years; HR, 0.95;
4 236 (14) 247 (15) 95% CI, 0.77-1.16).
5 (least deprived) 366 (22) 357 (21) Adjustment for baseline character-
Ankle brachial index, mean (SD) 0.86 (0.09) 0.86 (0.09) istics did not affect the HR for the pri-
Blood pressure, mean (SD), mm Hg mary end point (HR, 1.00; 95% CI,
Systolic 148 (22) 147 (22) 0.81-1.23). Comparisons of the pri-
Diastolic 84 (11) 84 (11) mary end point by sex, age, and ABI cut-
Serum total cholesterol, mg/dL 238.7 (41.3) 238.2 (42.4) points are shown in TABLE 3. Event
Smoking status, No. (%) rates were higher in older men and in
Current 547 (33) 538 (32)
Previous c 542 (32) 564 (34)
those with a lower ABI cut point, but
Never 586 (35) 573 (34)
no significant differences were found
Diabetes mellitus, No. (%) d 45 (3) 43 (3)
in the HRs. Excluding participants with
Medication, No. (%) diabetes, the event rate per 1000 person-
Diuretic 260 (15.5) 251 (15.0) years in the aspirin group was 13.7
␤-Blocker 168 (10.0) 161 (9.6) (95% CI, 11.7-15.9) and in the pla-
Nitrate/calcium channel blocker 110 (6.6) 106 (6.3) cebo group was 12.8 (95% CI, 10.9-
ACE inhibitor/angiotensin II antagonist 105 (6.3) 102 (6.1) 14.9; HR, 1.07; 95% CI, 0.87-1.33).
Lipid-lowering agents 69 (4.1) 73 (4.4) Participants adhered to the study
Abbreviation: ACE, angiotensin-converting enzyme. medication for 60% of person-years of
SI conversion factor: To convert total serum cholesterol from mg/dL to mmol/L, multiply by 0.0259.
a Data complete except cholesterol (1664 in aspirin group and 1666 in placebo group). follow-up (up to death, vascular or ad-
b Based on Scottish Index of Multiple Deprivation which assigns each postcode of residence to deprivation score de-
rived from levels of income, employment, health, education, access to services, housing, and crime.10
verse event, or end of trial). More than
c Smokers who had stopped smoking for at least 6 months before randomization.
d Self-reported.
85% of the participants took the medi-
cation for at least 6 months. The effect
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 ASPIRIN AND PREVENTION IN LOW ANKLE BRACHIAL INDEX

of aspirin vs placebo on the primary end
point was not significantly different
(P=.31) between those who were still
taking their medication at 5 years (as-
pirin, 10.9; 95% CI, 8.6-13.6 vs pla-
cebo, 11.9; 95% CI, 9.5-14.6 events per
1000 person-years; HR, 0.92; 95% CI,
0.68-1.24) and those not taking their
medication (aspirin, 17.2; 95% CI, 14.0-
20.8 vs placebo, 15.1; 95% CI, 12.2-
18.6 events per 1000 person-years; HR,
1.14; 95% CI, 0.86-1.51). At the 5-year
follow-up, those taking their medica-
tion did so for 88% of person-years
rate (following self-exclusion for clini- cular events in primary prevention trials
cal cardiovascular disease) and be- have been shown to be comparable in
cause of a lower population distribu- men and women,9 suggesting that sex
tion of the ABI in women than in imbalance in this trial was unlikely to
men17,18 leading to higher levels of trial have affected greatly the results.
eligibility among women. However, The rate of major cardiovascular and
both the relative risk of a cardiovascu- cerebrovascular events was lower than
lar event for a given level of ABI2 and expected, consistent with recent de-
the proportional risk reduction for vas- creases in event rates in Scotland as a
Figure 2. Primary End Point Event by Treatment Group and Duration of Follow-up
0.14
Aspirin

Proportion With Primary End Point Event

Placebo
throughout the entire trial, whereas 0.12

those classified as not taking their medi-

0.10
cation did so for 24% of person-years.
0.08
Adverse Events
TABLE 4 shows that 34 participants 0.06
(2.0%) in the aspirin group had an ini-
0.04
tial event of a major hemorrhage com-
pared with 20 (1.2%) in the placebo 0.02
group (aspirin, 2.5; 95% CI; 1.7-3.5 vs HR 1.03 (95% CI, 0.84-1.27)
placebo, 1.5; 95% CI, 0.9-2.3 per 1000
0 2 4 6 8 10
person-years; HR, 1.71; 95% CI, 0.99- Time, y
2.97). Of these events, 11 in the aspi-
No. at risk
rin group and 7 in the placebo group Aspirin 1675 1618 1555 1473 946 124
were intracranial including 3 fatal sub- Placebo 1675 1634 1566 1474 935 119

arachnoid or subdural hemorrhages in These data represent the initial event only. Primary end point events comprised fatal or nonfatal coronary event,
the aspirin group compared with none stroke, or revascularization. CI indicates confidence interval; HR, hazard ratio.
in the placebo group. Differences in
total number of adverse events be- Table 2. Vascular End Point Events in Participants Randomized to Aspirin or Placebo
tween groups were similar but less No. (%) of Participants With Event [95% CI]
marked than for initial events.
Aspirin Group Placebo Group
COMMENT (n = 1675) (n = 1675)
Primary end point event a 181 (10.8) [9.4-12.4] 176 (10.5) [9.1-12.1]
To our knowledge, this trial is the Fatal
first to report on the effectiveness of Coronary event 28 (1.7) [1.2-2.4] 18 (1.1) [0.7-1.7]
aspirin in reducing major cardiovas- Stroke b 7 (0.4) [0.2-0.9] 12 (0.7) [0.4-1.2]
cular and cerebrovascular events in Nonfatal
individuals from the general popula- Myocardial infarction 62 (3.7) [2.9-4.7] 68 (4.1) [3.2-5.1]
tion who were free of clinical cardio- Stroke b 37 (2.2) [1.6-3.0] 38 (2.3) [1.7-3.1]
vascular disease but at higher risk as Coronary revascularization c 24 (1.4) [1.0-2.1] 20 (1.2) [0.8-1.8]
identified by ABI screening. We did Peripheral revascularization d 23 (1.4) [0.9-2.1] 20 (1.2) [0.8-1.8]
not observe a reduction in major vas- Secondary end point event e 288 (17.2) [15.5-19.1] 290 (17.3) [15.6-19.2]
Angina 72 (4.3) [3.4-5.4] 64 (3.8) [3.0-4.8]
cular events or in the secondary vas-
Intermittent claudication 53 (3.2) [2.4-4.1] 53 (3.2) [2.4-4.1]
cular end point, which also included
Transient ischemic attack 38 (2.3) [1.7-3.1] 41 (2.4) [1.8-3.3]
angina, intermittent claudication, and
Abbreviation: CI, confidence interval.
transient ischemic attack. a Initial primary event only.
b Fatal strokes include 2 ischemic, 3 hemorrhagic, 2 unknown in aspirin group; 7 ischemic, 3 hemorrhagic, 2 unknown in
A number of factors may have con- placebo group. Nonfatal strokes include 28 ischemic, 2 hemorrhagic, 7 unknown in aspirin group; 30 ischemic, 1 hem-
tributed to these findings. Approxi- orrhagic, 7 unknown in placebo group.
c Includes coronary artery bypass surgery, angioplasty, or stent.
mately, 70% of trial participants were d Includes carotid and lower limb surgery, angioplasty, or stent.
e Initial event only which includes events as in primary end point, plus angina, intermittent claudication, and transient isch-
women because men responded to the
aemic attack.
screening invitation at a slightly lower
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 ASPIRIN AND PREVENTION IN LOW ANKLE BRACHIAL INDEX

whole. However, given that the over- having diabetes at baseline and analy- the Anti-Thrombotic Trialists’ Collabo-
all 10-year event rate (equivalent to sis excluding these individuals did not ration,9 aspirin led to a smaller propor-
12.7%) was within the accepted me- meaningfully change the results. tional risk reduction of 19% in serious
dium cardiovascular risk category A likely major effect on our find- vascular events in the secondary pre-
(10%-20%), this was unlikely to ex- ings was the limited power of the study vention trials and only a 12% reduc-
plain fully the lack of an effect of aspi- to detect a small effect of aspirin. A tion in the primary prevention trials.24-29
rin. Also, the inclusion of participants meta-analysis of secondary preven- A formal comparison however found
with diabetes mellitus could have in- tion trials of aspirin use among pa- no significant difference in effective-
fluenced our results (aspirin has been tients with symptomatic peripheral ar- ness between the primary and second-
shown to have no effect on vascular tery disease found a 25% proportional ary prevention trials (test for hetero-
events in asymptomatic patients with risk reduction in cardiovascular events, geneity P ⱖ .1). 9 In light of these
diabetes,19-21 and diabetes may inhibit although this result was not statisti- findings, our initial estimate of a 25%
the antiplatelet effect of aspirin22), but cally significant.23 In the recent indi- reduction in event rate in this trial,
only 3% of trial participants reported vidual participant data meta-analysis by based on evidence at that time, was
likely to have been an overestimate. Sta-
Table 3. Primary End Point Events by Age, Sex, and Ankle Brachial Index tistical power was greater for the sec-
Participants With Event ondary end point analysis. However,
lack of a statistically significant effect
Aspirin Group Placebo Group
(n = 1675) (n = 1675) of aspirin for this outcome could in part
be explained if aspirin has a lesser effect
Per 1000 Per 1000 on chronic atherosclerotic narrowing
Person-Years Person-Years Hazard Ratio
Subgroup No. (95% CI) No. (95% CI) (95% CI) (typical of angina and intermittent clau-
Age, y dication) than on acute thrombotic or
⬍62 57 8.6 (6.5-11.2) 70 10.2 (8.0-12.9) 0.85 (0.60-1.20) embolic events.
ⱖ62 124 18.8 (15.6-22.4) 106 16.6 (13.6-20.1) 1.13 (0.87-1.47) Although we found no statistically
Sex significant effect of aspirin on major
Men 96 27.4 (22.2-33.5) 83 23.9 (19.0-29.6) 1.15 (0.86-1.54)
Women 85 8.8 (7.0-10.8) 93 9.6 (7.7-11.7) 0.92 (0.68-1.23)
events, the HRs and 95% CIs did not
ABI
rule out the possibility of a risk reduc-
ⱕ0.95 181 13.7 (11.8-15.9) 176 13.3 (11.4-15.4) 1.03 (0.84-1.27) tion of up to 16% (or an increased risk
ⱕ0.90 134 15.7 (13.2-18.6) 134 15.5 (12.9-18.3) 1.02 (0.80-1.29) of up to 27%). However, extrapolat-
ⱕ0.85 78 18.6 (14.7-23.2) 82 18.8 (14.9-23.3) 0.99 (0.73-1.35) ing from the numbers screened for par-
ⱕ0.80 53 24.3 (18.2-31.8) 57 23.0 (17.4-29.8) 1.06 (0.73-1.54) ticipation in our trial, a risk reduction
Abbreviations: ABI, ankle brachial index; CI, confidence interval. of this order means that between 500
and 600 people from the general popu-
Table 4. Adverse Events in Participants Randomized to Aspirin or Placebo
lation would need to be screened and
prescribed aspirin to prevent a single
No. (%) of Participants With Total Adverse
Adverse Event, 95% [CI] a Events, b No. major cardiovascular event over an
8-year period. It is highly question-
Aspirin Placebo
Aspirin Group Placebo Group Group Group able whether the additional resources
(n = 1675) (n = 1675) (n = 65) (n = 59) required to screen and treat such a large
Major hemorrhage 34 (2.0) [1.5-2.8] 20 (1.2) [0.8-1.8] 39 32 number of people to prevent only a
Hemorrhagic stroke, No. c small number of events would be jus-
Fatal 3 3 3 4
tified or indeed whether a larger trial
Nonfatal 2 1 2 1
to try and demonstrate such a small
Subarachnoid/subdural, No. c
Fatal 3 0 3 0 effect should be considered. In addi-
Nonfatal 3 3 3 4 tion, any effect of aspirin on cardiovas-
Gastrointestinal, No. d 9 8 13 14 cular events needs to be balanced
Other, No. d 14 5 15 9 against the potential for harm. Al-
Gastrointestinal ulcer 14 (0.8) [0.5-1.4] 8 (0.5) [0.2-0.9] 15 11 though numbers were small, the trial
Retinal hemorrhage 1 (0.1) [0.0-0.3] 4 (0.2) [0.1-0.6] 1 5 results suggested an increased inci-
Severe anemia 6 (0.4) [0.2-0.8] 10 (0.6) [0.3-1.1] 10 11 dence of major hemorrhage and gas-
a Initial primary, secondary, or adverse event. trointestinal ulcer, although not se-
b Includes all adverse events except repeat of same event in any given participant.
c Diagnosis based on brain scan. vere anemia, in the aspirin group, and
d Required admission to hospital to control bleeding. Admission only to investigate bleeding was not included as major
more participants in the aspirin group
hemorrhage.
than in the placebo group had fatal in-
846 JAMA, March 3, 2010—Vol 303, No. 9 (Reprinted) ©2010 American Medical Association. All rights reserved.

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tracranial adverse events. These find-
ings are compatible with previous pri-
mary prevention trials in which a
collective 50% increase was found in
major gastrointestinal and other extra-
cranial bleeds.9 Such adverse effects are
of particular concern in the context of
screening the healthy general popula-
tion and when the absolute effects of
aspirin in reducing major vascular
events may be small.
In our trial, study medication was
taken for 60% of trial person-years, with
more than 85% of participants taking
aspirin for 6 months or more. Similar
findings were reported in a compa-
rable study of antithrombotic agents in-
volving high-risk men recruited from
UK general practices.26 Also, in a trial
of aspirin on Italian general practi-
tioner attendees with one or more car-
diovascular risk factor, nearly 20%
stopped medication within a year.28 Al-
though no significant interaction of the
effect of aspirin on the primary end
point was found between those taking
or not taking the treatment medica-
tion, this result was based on small
numbers, and stopping medication
would undoubtedly have influenced the
trial results. However, given that the
trial population was typical of the lo-
cal population and was followed up
closely, it is doubtful that the propor-
tion receiving treatment could be im-
proved if an ABI screening was ever
implemented in the community. The
likely effect of aspirin in a general popu-
lation screened for ABI must therefore
be taken to include the effect of mod-
erate adherence to treatment, as did the
results of this trial. The reasons for stop-
ping medication in the trial were much
as expected, including taking aspirin for
noncardiovascular reasons, known ad-
verse effects of aspirin, other illnesses
unrelated to aspirin, and no longer
wanting to take the study medica-
tion.16 These factors may have been
compounded by a lack of understand-
ing of the ABI as a measure of risk.30
An ABI of 0.90 or less is often used
as the cut point for identifying indi-
viduals at high risk of peripheral ath-
erosclerosis. However, the risk of fu-
©2010 American Medical Association. All rights reserved.
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ASPIRIN AND PREVENTION IN LOW ANKLE BRACHIAL INDEX
ture vascular events is a reverse J-shaped
curve with a level of 1.1 to 1.4 being
considered normal.2 In ABI screening
the cut point selected is a trade-off be-
tween level of risk and yield of indi-
viduals who might potentially benefit
from treatment. We considered that a
cut point of 0.95 was preferred given
an estimated absolute increase in yield
of 6% of the screened population. This
choice of cut point could theoretically
have affected the result of the trial.
However, the major event rate was not
very much higher among those with an
ABI of 0.90 or less (15.6 per 1000 per-
son-years, 95% CI, 13.8-17.6) than
among those with an ABI of 0.95 or less
(13.5 per 1000 person-years, 95% CI,
12.2-15.0). Also, no substantial differ-
ences in the effects of aspirin on the pri-
mary end point were found for differ-
ent ABI cut points, although numbers
were small for such an analysis.
Although this trial was not of screen-
ing per se, the results indicate that using
the ABI in the community to screen in-
dividuals free of cardiovascular dis-
ease for an ABI of 0.95 or less is un-
likely to be beneficial if aspirin is the
intervention of choice. However, given
the increased level of risk among those
with a low ABI, the use of alternative
therapies, such as statins or more po-
tent antiplatelet agents without atten-
dant hemorrhagic risks may usefully be
considered.31-33 In addition, given that
the trial was a pragmatic trial in the con-
text of ABI screening in the general
population, aspirin might still have a
net beneficial effect on patients with a
low ABI, elevated risk factors, and a
greater incentive to continue taking
medication. Further trials of the man-
agement of patients with a low ABI
identified in clinical practice as part of
cardiovascular risk assessment pro-
grams would be justified.
Author Contributions: Drs Fowkes and Price as co-
first authors had full access to all of the data in the
study and take responsibility for the integrity of the
data and the accuracy of the data analysis.
Study concept and design: Fowkes, Price, Sandercock,
Lowe, Murray.
Acquisition of data: Stewart.
Analysis and interpretation of data: Fowkes, Price,
Butcher, Leng, Pell, Sandercock, Fox, Murray.
Drafting of the manuscript: Fowkes, Price.
(Reprinted) JAMA, March 3, 2010—Vol 303, No. 9
Critical revision of the manuscript for important in-
tellectual content: Fowkes, Price, Stewart, Butcher,
Leng, Pell, Sandercock, Fox, Lowe, Murray.
Statistical analysis: Butcher, Murray.
Obtained funding: Fowkes, Price, Lowe, Murray.
Administrative, technical, or material support: Stewart,
Leng, Pell, Sandercock.
Study supervision: Fowkes, Price, Sandercock, Lowe,
Murray.
Financial Disclosures: Drs Fowkes and Price re-
ported that they have received research support from
Bayer HealthCare. Drs Fowkes and Sandercock re-
ported that they have received lecture fees and ex-
penses from Bayer HealthCare. Dr Fowkes reported
that he has received research support and honoraria
from Sanofi-Aventis and Bristol-Myers Squibb. No other
authors reported disclosures.
Committees and Other Contributing Groups: Steer-
ing Committee: F. G. R. Fowkes (chair), M. Bain, R.
Clements, J. Darnborough, I. J. Deary, K. A. A. Fox,
G. C. Leng, G. D. O. Lowe, E. Mallinson, G. D. Mur-
ray, A. C. H. Pell, J. F. Price, A. Rumley, P. A. G. Sand-
ercock, and J. Wrench. Management Committee: M.
Bree, S. Cudmore, A. F. Douglas, M. C. W. Stewart,
S. A. Wilson, E. M. Armstrong, F. G. R. Fowkes, G. D.
Murray, and J. F. Price. Writing Committee: F. G. R.
Fowkes, J. F. Price, M. C. W. Stewart, I. Butcher, G.
C. Leng, A. C. H. Pell, P. A. G. Sandercock, K. A. A.
Fox, G. D. O. Lowe, and G. D. Murray. Data Moni-
toring Committee S. M. Cobbe (chair), I. Ford, and
C. P. Warlow. Outcome Events Committee: J. Bray,
E. Bream, M. Bree, F. G. R. Fowkes, V. Katikireddi, R.
Lindley, J. Morling, D. Northridge, J. F. Price, C. A.
M. Ritchie, T. Sommerfield, and R. Walton. Data Col-
lection: E. Tolmie, E. C. Graham, J. F. Alexander, H.
Lawrie, E. M. Armstrong, I. F. Tierney, S. A. Wilson,
P. Ross, F. Reston, D. Willis, E. M. Kerracher, F. J. Neary,
F. B. Smith, K. Hepburn, C. D. Rea, H. Mackay, W.
A. Smith, C. D. Martin, C. A. M. Ritchie, L. Paton, M.
C. W. Stewart, and staff at Wellcome Trust Clinical
Research Facility, Edinburgh. Data Handling: E. Healy,
H. Peterson, E. Crooks, L. Gardner, J. Hay, E. M. Ker-
racher, N. Kerracher, C. Maguire, A. Sloan, D. Thom,
and L. C. McGoohan. Blood Assays and Pharmacy:
A. Rumley, J. Patterson, G. Baxter, R. Spooner, E. Foley,
and J. Carracher. Statistical Analysis: I. Butcher, G. S.
McHugh, R. Lee, and G. D. Murray.
Funding/Support: The trial was funded by the British
Heart Foundation and Chief Scientist’s Office, Scot-
land. Bayer HealthCare provided the aspirin and pla-
cebo tablets and funds for packaging, dispensing, and
some statistical analysis.
Role of the Sponsor: The funders had no role in the
design and conduct of the study; collection, man-
agement, analysis and interpretation of the data;
and preparation, review, or approval of the manu-
script. The trial steering committee independently
made all decisions on the conduct of the trial. A
representative from Bayer HealthCare was permit-
ted to attend steering committee meetings as an
observer.
Online-Only Material: An eFigure and eSupplemen-
tary Material are available at http://www.jama.com.
REFERENCES
1. Newman AB, Siscovick DS, Manolio TA, et al; Car-
diovascular Heart Study (CHS) Collaborative Re-
search Group. Ankle-arm index as a marker of ath-
erosclerosis in the Cardiovascular Health Study.
Circulation. 1993;88(3):837-845.
2. Fowkes FG, Murray GD, Butcher I, et al; Ankle Bra-
chial Index Collaboration. Ankle brachial index com-
bined with Framingham Risk Score to predict cardio-
vascular events and mortality: a meta-analysis. JAMA.
2008;300(2):197-208.
3. Ebrahim S, Smith GD. Systematic review of ran-
domised controlled trials of multiple risk factor inter-
847
 ASPIRIN AND PREVENTION IN LOW ANKLE BRACHIAL INDEX
ventions for preventing coronary heart disease. BMJ.
1997;314(7095):1666-1674.
4. Manuel DG, Lim J, Tanuseputro P, et al. Revisit-
ing Rose: strategies for reducing coronary heart disease.
BMJ. 2006;332(7542):659-662.
5. Hirsch AT, Haskal ZJ, Hertzer NR, et al; American
Association for Vascular Surgery; Society for Vascu-
lar Surgery; Society for Cardiovascular Angiography
and Interventions; Society for Vascular Medicine and
Biology; Society of Interventional Radiology; ACC/
AHA Task Force on Practice Guidelines Writing Com-
mittee to Develop Guidelines for the Management
of Patients With Peripheral Arterial Disease; Ameri-
can Association of Cardiovascular and Pulmonary
Rehabilitation; National Heart, Lung, and Blood
Institute; Society for Vascular Nursing; TransAtlantic
Inter-Society Consensus; Vascular Disease Foundation.
ACC/AHA 2005 practice guidelines for the manage-
ment of patients with peripheral arterial disease (lower
extremity, renal, mesenteric, and abdominal aortic).
Circulation. 2006;113(11):e463-e654.
6. Norgren L, Hiatt WR, Dormandy JA, et al. Inter-
society consensus for the management of peripheral
arterial disease (TASC II). J Vasc Surg. 2007;45
(suppl S):S5-S67.
7. US Preventive Services Task Force. Screening for
peripheral arterial disease: recommendation statement.
Rockville, MD: Agency for Healthcare Research and
Quality; August 2005. AHRQ Publication No.
05-0583-A-EF. http://www.ahrq.gov/clinic/uspstf05
/pad/padrs.htm. Accessed July 15, 2009.
8. Antithrombotic Trialists’ Collaboration. Collabora-
tive meta-analysis of randomised trials of antiplatelet
therapy for prevention of death, myocardial infarc-
tion and stroke in high risk patients [published cor-
rection appears in BMJ. 2002;324(7330):141]. BMJ.
2002;342(7329):71-86.
9. Baigent C, Blackwell L, Collins R, et al; Antithrom-
botic Trialists’ (ATT) Collaboration. Aspirin in the pri-
mary and secondary prevention of vascular disease:
collaborative meta-analysis of individual participant
data from randomised trials. Lancet. 2009;373
(9678):1849-1860.
10. Office of the Chief Statistician, Scottish Executive.
Scottish Index of Multiple Deprivation 2006 Techni-
cal Report. http://www.scotland.gov.uk/Resource
/doc/933/0041180.pdf. Accessed July 15, 2009.
11. Gillum RF, Fortmann SP, Prineas RJ, Kottke TE.
International diagnostic criteria for acute myocardial
infarction and acute stroke. Am Heart J. 1984;
108(1):150-158.
12. Ogren M, Hedblad B, Isacsson S-O, Janzon L,
848 JAMA, March 3, 2010—Vol 303, No. 9 (Reprinted)
Downloaded From: http://jama.jamanetwork.com/ on 02/16/2014
Jungquist G, Lindell S-E. Non-invasively detected ca-
rotid stenosis and ischaemic heart disease in men with
leg arteriosclerosis. Lancet. 1993;342(8880):1138-
1141.
13. Leng GC, Lee AJ, Fowkes FGR, et al. Incidence,
natural history and cardiovascular events in sympto-
matic and asymptomatic peripheral arterial disease in
the general population. Int J Epidemiol. 1996;
25(6):1172-1181.
14. Hooi JD, Kester AD, Stoffers HE, Rinkens PE,
Knottnerus JA, van Ree JW. Asymptomatic periph-
eral arterial occlusive disease predicted cardiovascu-
lar morbidity and mortality in a 7-year follow up study.
J Clin Epidemiol. 2004;57(3):294-300.
15. Antiplatelet Trialists’ Collaboration. Collabora-
tive overview of randomised trials of antiplatelet
therapy, I: prevention of death, myocardial infarc-
tion, and stroke by prolonged antiplatelet therapy in
various categories of patients. BMJ. 1994;308
(6921):81-106.
16. Price JF, Stewart MC, Deary IJ, et al; AAA Trialists.
Low dose aspirin and cognitive function in middle aged
to elderly adults: randomised controlled trial. BMJ.
2008;337:a1198. doi:10.1136/bmj.a1198.
17. Price JF, Stewart MCW, Douglas A, Murray GD,
Fowkes FGR. Frequency of a low ankle brachial in-
dex in the general population by age, sex and depri-
vation: cross sectional survey of 28,980 men and
women. Eur J Cardiovasc Prev Rehabil. 2008;15
(3):370-375.
18. Fowkes FGR, Housley E, Cawood EHH, Macintyre
CCA, Ruckley CV, Prescott RJ. Edinburgh Artery Study:
prevalence of asymptomatic and symptomatic periph-
eral arterial disease in the general population. Int J
Epidemiol. 1991;20(2):384-392.
19. ETDRS investigators. Aspirin effects on mortality
and morbidity in patients with diabetes mellitus: Early
Treatment Diabetic Retinopathy Study Report 14.
JAMA. 1992;268(10):1292-1300.
20. Ogawa H, Nakayama M, Morimoto T, et al; Japa-
nese Primary Prevention of Atherosclerosis With As-
pirin for Diabetes ( JPAD) Trial Investigators. Low-
dose aspirin for primary prevention of atherosclerotic
events in patients with type 2 diabetes: a random-
ized controlled trial. JAMA. 2008;300(18):2134-
2141.
21. Belch J, MacCuish A, Campbell I, et al. The pre-
vention of progression of arterial disease and diabe-
tes (POPADAD) trial: factorial randomised placebo con-
trolled trial of aspirin and antioxidants in patients with
diabetes and asymptomatic peripheral arterial disease.
BMJ. 2008;337a:1840. doi:10.1136/bmj.a1840.
©2010 American Medical Association. All rights reserved.
22. Ajjan R, Storey RF, Grant PJ. Aspirin resistance and
diabetes mellitus. Diabetologia. 2008;51(3):385-
390.
23. Berger JS, Krantz MJ, Kittelson JM, Hiatt WR. As-
pirin for the prevention of cardiovascular events in pa-
tients with peripheral artery disease. JAMA. 2009;
301(18):1909-1919.
24. Peto R, Gray R, Collins R, et al. Randomised trial
of prophylactic daily aspirin in British male doctors.
Br Med J (Clin Res Ed). 1988;296(6618):313-316.
25. Steering Committee of the Physicians’ Health Study
Research Group. Final report on the aspirin compo-
nent of the ongoing Physicians Health Study. N Engl
J Med. 1989;321(3):129-135.
26. The Medical Research Council’s General Prac-
tice Research Framework. Thrombosis prevention trial:
randomised trial of low-intensity oral anticoagula-
tion with warfarin and low-dose aspirin in the pri-
mary prevention of ischaemic heart disease in men at
increased risk. Lancet. 1998;351(9098):233-241.
27. Hansson L, Zanchetti A, Carruthers SG, et al; HOT
Study Group. Effects of intensive blood-pressure low-
ering and low-dose aspirin in patients with hyperten-
sion: principal results of Hypertension Optimal Treat-
ment (HOT) randomised trial. Lancet. 1998;351
(9118):1755-1762.
28. de Gaetano G; Collaborative Group of the Pri-
mary Prevention Project. Low-dose aspirin and vita-
min E in people at cardiovascular risk: a randomised
trial in general practice. Lancet. 2001;357(9250):
89-95.
29. Ridker PM, Cook NR, Lee IM, et al. A random-
ized trial of low-dose aspirin in the primary preven-
tion of cardiovascular disease in women. N Engl J Med.
2005;352(13):1293-1304.
30. Eborall HC. Lay Attitudes Towards Cardiovascu-
lar Risk in the Context of Screening, Prevention, and
Trial Participation [dissertation]. Edinburgh, Scot-
land: University of Edinburgh; 2004.
31. Pickin DM, McCabe CJ, Ramsay LE, et al. Cost
effectiveness of HMG-CoA reductase inhibitor (stat-
in) treatment related to the risk of coronary heart dis-
ease and cost of drug treatment. Heart. 1999;
82(3):325-332.
32. CAPRIE Steering Committee. A randomised,
blinded trial of clopidogrel versus aspirin in patients
at risk of ischaemic events (CAPRIE). Lancet. 1996;
348(9038):1329-1339.
33. Bhatt DL, Fox KAA, Hacke W, et al; CHARISMA
Investigators. Clopidogrel and aspirin versus aspirin dose
for the prevention of atherothrombotic events. N Engl
J Med. 2006;354(16):1706-1717.