Statin Use and Leg Functioning in Patients With and
Without Lower-Extremity Peripheral Arterial Disease
Mary McGrae McDermott, MD; Jack M. Guralnik, MD, PhD; Philip Greenland, MD;
William H. Pearce, MD; Michael H. Criqui, MD, MPH; Kiang Liu, PhD; Lloyd Taylor, MD;
Cheeling Chan, MS; Leena Sharma, MD; Joseph R. Schneider, MD; Paul M Ridker, MD;
David Green, MD, PhD; Maureen Quann, BS
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Background—We determined whether statin use (versus nonuse) is associated with superior lower-extremity functioning
independently of cholesterol levels and other confounders in patients with and without peripheral arterial disease.
Methods and Results—Participants included 392 men and women with an ankle brachial index (ABI) ⬍0.90 and 249 with
ABI 0.90 to 1.50. Functional outcomes included 6-minute walk distance and 4-meter walking velocity. A summary
performance score combined performance in walking speed, standing balance, and time for 5 repeated chair rises into
an ordinal score ranging from 0 to 12 (12⫽best). Adjusting for age, sex, ABI, comorbidities, education level, medical
insurance status, cholesterol, and other confounders, participants taking statins had better 6-minute walk performance
(1276 versus 1218 feet, P⫽0.045), faster walking velocity (0.93 versus 0.89 m/s, P⫽0.006), and a higher summary
performance score (10.2 versus 9.4, P⬍0.001) than participants not taking statins. Positive associations were attenuated
slightly after additional adjustment for C-reactive protein level but remained statistically significant for walking velocity
and the summary performance score. We did not find significant associations between lower-extremity functioning and
aspirin, ACE inhibitors, vasodilators, or ␤-blockers.
Conclusions—Statin use is associated with superior leg functioning compared with no statin use, independent of
cholesterol levels and other potential confounders. These data suggest that non– cholesterol-lowering properties of
statins may favorably influence functioning in persons with and without peripheral arterial disease. (Circulation. 2003;
107:757-761.)
Key Words: statins 䡲 peripheral vascular disease 䡲 inflammation
H
MG-Co-A reductase inhibitor drugs (statins) have beneficial effects on atherosclerosis beyond those related to
cholesterol lowering.1– 6 Statins stabilize atherosclerotic
plaques, reduce oxidative stress, and decrease vascular inflammation.1,2 In vascular endothelium, statins increase concentrations of nitric oxide, which has vasodilator, antithrombotic, and antiproliferative properties.1 These beneficial
properties may contribute to the reduction in cardiac and
cerebrovascular events in patients treated with statins.
Men and women with lower-extremity peripheral arterial
disease (PAD) have impaired functioning compared with
those without PAD.7 Greater PAD severity, as measured by
the ankle brachial index (ABI), is associated with more
extensive functional impairment.7 Although favorable effects
of statins, acting on lower-extremity arterial obstruction, may
improve PAD-related functional impairment, such associations have not been studied previously to our knowledge.
Because of the direct actions of statins on endothelial func-
tion, we hypothesized that statin use might improve lowerextremity functioning in patients with and without PAD. We
therefore sought to determine whether statin use (versus
nonuse) would be associated with better functioning, independent of cholesterol levels and other possible confounding
factors in a cohort of patients with and without PAD. Because
statin use may be a marker of better health care access or
quality, we also assessed relations between ␤-blocker, aspirin, ACE inhibitors, and vasodilator use with functioning.
Methods
Participant Identification
The protocol was approved by the institutional review boards at
Northwestern University’s Feinberg School of Medicine and Catholic Health Partners Hospital. All participants gave informed consent. Participants were age 55 years and older.
PAD was defined as ABI ⬍0.90.7–9 Absence of PAD was defined
as ABI ⱖ0.90 and ⱕ1.50.7–9 PAD participants were identified from
consecutive patients with PAD documented in 3 Chicago-area
Received August 27, 2002; revision received October 14, 2002; accepted October 21, 2002.
From Feinberg School of Medicine at Northwestern University (M.M.M., P.G., W.H.P., K.L., C.C., L.S., J.R.S., D.G., M.Q.), Chicago, Ill; Laboratory
of Epidemiology, Demography, and Biometry (J.M.G.), National Institute on Aging, Bethesda, Md; University of California at San Diego (M.H.C.), San
Diego, Calif; Oregon Health Sciences Medical Center (L.T., C.C.), Portland, Ore; Evanston Hospital (J.R.S.), Evanston, Ill; and Brigham and Women’s
Hospital (P.M.R.), Harvard Medical School, Boston, Mass.
Correspondence to Mary McGrae McDermott, MD, 675 N St Clair, Suite 18-200, Chicago, IL 60611. E-mail mdm608@northwestern.edu
© 2003 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/01.CIR.0000050380.64025.07
757
758
Circulation
February 11, 2003
noninvasive vascular laboratories between January 1, 1997, and the
fall of 1999. These participants had both newly and previously
diagnosed PAD. A few were identified from among consecutively
identified patients in a large general internal medicine (GIM)
practice who were screened with the ABI. Participants without PAD
were identified from among consecutive patients with normal lowerextremity arterial tests in the 3 noninvasive vascular laboratories and
from consecutive patients with appointments in the GIM practice that
were screened with the ABI. Study visits took place between October
1998 and January 2000.
All prescription and over-the-counter medications were recorded.
Doses were not recorded. The principal investigator (M.M.M.)
classified medications as follows: statins, aspirin, ␤-blockers, ACE
inhibitors, and vasodilators. The principal investigator was blinded
to all other participant data when medications were classified into
categories.
Exclusion Criteria
Functional Measures
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Individuals with ABI ⬎1.50 were excluded, because this indicates
poorly compressible leg arteries and inability to gauge arterial
obstruction accurately.7–9 Individuals with an abnormal ABI at the
noninvasive vascular laboratory who had a normal ABI at their study
visit were excluded. Individuals originally found to have normal
lower-extremity arterial studies at the noninvasive vascular laboratory with ABI ⬍0.90 at the study visit were also excluded. The
number of participants excluded because their ABI was either ⱖ1.50
or not consistent with vascular laboratory test results was 151.
Patients with dementia were excluded because of their inability to
answer questions accurately (n⫽7). Nursing home residents (n⫽65),
wheelchair-bound patients (n⫽33), and patients with foot or leg
amputations (n⫽80) were excluded because they have severely
impaired functioning. Non–English-speaking patients were excluded
because investigators were not fluent in non-English languages
(n⫽61). Patients with recent major surgery were excluded (n⫽5).
Ankle Brachial Index Measurement
After participants rested supine for 5 minutes, a hand-held Doppler
probe (Nicolet Vascular Pocket Dop II) was used to measure systolic
pressures in the right brachial artery, right dorsalis pedis and
posterior tibial arteries, left dorsalis pedis and posterior tibial
arteries, and left brachial artery. Pressures were measured twice, in
the order listed and then in reverse order. ABIs were calculated by
dividing average pressures in each leg by the average of the four
brachial pressures.9 Average brachial pressures in the arm with
highest pressure were used when one brachial pressure was higher
than the opposite brachial pressure in both measurement sets, and the
two brachial pressures differed by ⱖ10 mm Hg in at least 1
measurement set. Lowest leg ABI was used in all analyses.
C-Reactive Protein Levels
C-reactive protein (CRP) levels were determined using an immunotechnique on the Behring BN II analyzer (Dade Behring). Monoclonal anti-CRP antibodies, coated on polystyrene beads, agglutinate
with CRP in the serum sample. Intensity of the resulting scattered
light in the nephelometer was used to determine the CRP content.
This assay detects CRP concentrations as low as 0.015 mg/dL.10
Cholesterol Levels
Total cholesterol levels were measured using enzymatic reaction
with peroxidase/phenol-4-aminoiphenazone indicator reaction.11 The
concentration of HDL-cholesterol was determined using a direct
enzymatic colorimetric assay.12
Comorbidities
Algorithms developed for the Women’s Health and Aging Study and
the Cardiovascular Health Study were used to document comorbidities.13 These algorithms combine data from patient report, physical
examination, medical record review, medications, laboratory values,
and a primary care physician questionnaire. Criteria developed by
the American College of Rheumatology were used to diagnose knee
and hip osteoarthritis.14,15 Comorbidities assessed were those known
or suspected to be associated with functioning and consisted of
angina, diabetes mellitus, myocardial infarction, stroke, heart failure,
pulmonary disease, knee arthritis, hip arthritis, hip fracture, spinal
stenosis, and disk disease.16 Angina, myocardial infarction, stroke,
and heart failure were combined into a heart disease and stroke
category. Knee arthritis, hip arthritis, hip fracture, spinal stenosis,
and disk disease were combined into an arthritis category.
Statin Use
Health interviewers collecting data on lower-extremity performance
were trained and certified by the study principal investigator
(M.M.M.) before data collection. Recertification occurred every 6
months. Health interviewers were unaware of study hypotheses
regarding statin use and leg functioning.
Six-Minute Walk
Following a standardized protocol, participants walk up and down a
100-foot hallway for 6 minutes after instructions to cover as much
distance as possible during 6 minutes.17 This test is highly reproducible among individuals with PAD (R⫽0.94).17
Summary Performance Score
The summary performance score is a global measure of lowerextremity functioning that predicts mobility loss, nursing home
placement, and mortality among community-dwelling older men and
women.18 –20 To calculate the summary performance score, a 0 to 4
score is assigned for performance on 4-meter walking velocity, time
to rise from a seated position 5 times, and standing balance,
respectively.18 –20 Individuals receive a zero score for each task they
are unable to complete. One to four scores for each task are assigned
based on quartiles of performance for ⬎5000 community dwelling
men and women participating in the Established Populations for the
Epidemiologic Study of the Elderly.18 –20 Scores are summed to
obtain the summary performance score, ranging from 0 to 12.
Four-Meter Walking Velocity
Walking velocity was measured with a 4-meter walk performed at
usual pace.18 –20 Each walk was performed twice. The faster walk in
each pair was used in analyses. Four-meter walk tests are highly
reproducible.21
Other Measurements
Body Mass Index
Height and weight were measured at the study visit. Body mass
index was calculated as weight (kg)/height2 (m2).
Education and Health Insurance Category
Education and type of health insurance were used as proxies for
socioeconomic status and were obtained by patient interview. Education was categorized as high school graduate or less, some college,
and college graduate or higher. Health insurance was categorized as
private, Medicare and private, Medicare, and Medicaid/no health
insurance.
Leg Symptoms
Leg symptoms were categorized using the San Diego claudication
questionnaire, based on a previous study.8 Leg symptom categories
were intermittent claudication, exertional leg pain/carry-on, atypical
exertional leg pain/stop, leg pain on exertion and rest, and no
exertional leg symptoms.8
Statistical Analyses
We used descriptive statistics to compare characteristics of statin
users versus statin nonusers. For continuous variables, statistical
significance of differences between statin users and nonusers was
evaluated using ANOVA. The statistical significance of differences
McDermott et al
TABLE 1.
Statin Use and Leg Functioning
759
Characteristics Among Men and Women Age 55 Years and Older According to Presence Versus Absence of Statin Use*
ABI ⬍0.90 (n⫽392)
Age, y
ABI ⱕ1.50 (n⫽641)
ABI 0.90 to 1.50 (n⫽249)
Taking
Statins
(n⫽177)
Not Taking
Statins
(n⫽215)
Taking
Statins
(n⫽75)
Not Taking
Statins
(n⫽174)
Taking
Statins
(n⫽252)
Not Taking
Statins
(n⫽389)
71.1 (8.7)
71.2 (7.8)
72.3 (9.0)
68.5 (7.6)
69.5 (8.2)
70.4 (7.8)
Male, %
63.8
60.5
62.7†
48.8†
63.5‡
55.3‡
African-American race, %
13.0
16.3
14.7
16.7
13.5
16.4
0.65 (0.14)
0.65 (0.15)
1.07 (0.11)†
1.10 (0.12)†
0.78 (0.23)§
0.85 (0.26)§
ABI
56.6
49.3
62.7
63.2
58.3
55.5
Cholesterol, mg/dL
Walking for exercise, %
170 (37.9)§
187 (37.3)§
167 (35.9)储
182 (36.7)储
169 (37.3)§
185 (37.0)§
HDL cholesterol, mg/dL
39.7 (13.6)
40.2 (16.3)
42.5 (12.6)
46.2 (17.2)
40.5 (13.3)
42.9 (16.9)
Smoking, pack-years
39.0 (34.3)
39.5 (35.7)
18.4 (28.7)
21.9 (28.8)
32.9 (34.0)
31.6 (33.9)
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Diabetes, %
29.4
33.9
24.0
17.8
27.8
26.7
Heart disease and stroke, %
70.6§
51.2§
58.7§
29.3§
67.1§
41.4§
Arthritis, %
36.2
41.4
53.3
59.8
41.3‡
49.6‡
0.22 (0.12–0.58)¶
0.35 (0.16–0.73)¶
0.33 (0.13–0.56)
0.24 (0.12–0.65)
0.26 (0.12–0.57)
0.30 (0.13–0.67)
CRP, mg/dL (median 关IQR兴)
Education
High school graduate or less, %
24.9储
39.5储
22.7
28.2
24.2¶
34.5¶
College graduate or higher, %
45.2‡
34.9‡
46.7
39.7
45.6#
37.0#
Private, %
24.3
20.5
32.0
31.0
26.6
25.2
Medicare⫹private, %
46.9
53.9
42.7
36.8
45.6
46.3
Medicare, %
26.0
19.1
21.3
24.1
24.6
21.3
2.8
6.5
4.0
8.0
Health insurance
Public aid/Medicaid/no health
insurance, %
3.2‡
7.2‡
*Values are expressed as mean (SD) unless otherwise indicated. IQR indicates interquartile range; HDL, high-density lipoprotein.
†P⬍0.05; ‡P⬍0.04; §P⬍0.001; 储P⬍0.002; ¶P⬍0.01; #P⬍0.03.
in dichotomous variables between statin users versus nonusers was
determined using ␹2 tests.
Differences in lower-extremity functioning between users and
nonusers for each drug category were evaluated using ANOVA,
adjusting for the known and potential confounders of age, race, sex,
educational level, health insurance status, body mass index, ABI,
total cholesterol, and comorbidities. Differences in functioning
between statin users and nonusers were determined, adjusting for the
aforementioned confounders and also CRP. This allowed us to
examine whether reduction of CRP levels by statins could mediate
relationships between statin use and leg functioning. Analyses were
performed among all participants, participants with ABI ⬍0.90, and
participants with ABI 0.90 to 1.49. Analyses were performed using
SAS Statistical Software version 8.2 (SAS Inc).
Results
Of 2662 potential participants identified from noninvasive
vascular laboratories, 220 were deceased, 464 could not be
located, 375 were ineligible, and 597 agreed to participate. Of
467 potential participants identified from the general medicine practice, 7 were deceased, 63 could not be located, 22
were ineligible, and 143 participated. Of 740 individuals
enrolled, 641 (86.6%) had blood samples taken for testing
and are included in these analyses.
Table 1 shows characteristics of participants according to
statin use versus nonuse and ABI category. Statin users
included higher proportions of men and had a higher prevalence of cardiovascular disease, a higher prevalence of
college graduates, lower cholesterol levels, and a lower
prevalence of arthritis compared with statin nonusers. Among
participants with ABI ⬍0.90, 34.2% had intermittent claudication, 20.4% were asymptomatic, and 45.4% had leg pain on
exertion and rest. Among participants with ABI ⬍0.90,
38.0% had a history of lower-extremity revascularization.
There were no significant differences in the prevalence of
each leg pain category or in the prevalence of revascularization between statin users versus nonusers.
In unadjusted analyses, the summary performance score
was significantly higher in statin users compared with nonusers among participants with ABI ⬍0.90 and in the entire
cohort (Table 2). There were no significant differences in
other functional measures between statin users and nonusers
in unadjusted analyses.
Adjusting for confounders, statin users had significantly
better functioning than statin nonusers among the entire
cohort for 6-minute walk performance (1276 versus 1218
feet, P⫽0.045), 4-meter walking velocity (0.93 versus 0.89
m/s, P⫽0.006), and the summary performance score (10.2
versus 9.4, P⬍0.001). Significant independent associations
between statin use and better lower-extremity functioning
were observed among participants with ABI ⬍0.90 for
4-meter walking velocity and the summary performance
score, adjusting for confounders. Among participants with
ABI 0.90 to 1.49, the summary performance score was
significantly higher in statin users than nonusers (10.6 versus
9.9, P⫽0.046).
760
TABLE 2.
Circulation
February 11, 2003
Differences in Functional Outcomes Among Participants According to Statin Use*
ABI ⬍0.90 (n⫽392)
Statin
Users
(n⫽177)
Statin
Nonusers
(n⫽215)
Six-minute walk distance, feet
1159 (369)
1098 (375)
Four-meter walking velocity, m/s
0.90 (0.18)
0.86 (0.22)
Summary performance score, (range, 0 to
12, 12⫽best)
10.1 (2.1)
9.0 (2.8)
Six-minute walk distance, feet
1157
Four-meter walking velocity, m/s
0.90
Summary performance score (range, 0 to
12, 12⫽best)
ABI ⱕ1.50 (n⫽641)
ABI 0.90 to 1.50 (n⫽249)
Statin
Users
(n⫽75)
Statin
Nonusers
(n⫽174)
P
Statin
Users
(n⫽252)
Statin
Nonusers
(n⫽389)
0.109
1458 (389)
0.057
0.98 (0.18)
1414 (425)
0.447
1247 (398)
1239 (427)
0.93 (0.22)
0.079
0.92 (0.19)
0.89 (0.22)
⬍0.001
10.6 (1.8)
10.0 (2.4)
0.055
10.2 (2.1)
9.4 (2.7)
⬍0.001
1100
0.86
0.114
1465
1408
0.255
1276
1218
0.045
0.028
0.98
0.93
0.055
0.93
0.89
10.0
0.006
9.0
⬍0.001
10.6
9.9
0.046
10.2
9.4
⬍0.001
Six-minute walk distance, feet)
Four-meter walking velocity, m/s
1151
1106
0.211
1461
1410
0.307
1271
1222
0.087
0.90
0.86
0.051
0.98
0.93
0.064
0.93
0.89
Summary performance score (range, 0 to
12, 12⫽best)
0.010
10.0
9.1
⬍0.001
10.6
9.9
0.048
10.2
9.4
⬍0.001
P
P
Unadjusted analyses
0.808
0.060
Adjusted for age, sex, race, educational level,
health insurance, BMI, ABI, total cholesterol,
heart disease and stroke, pulmonary disease,
diabetes, and arthritis
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Adjusted for age, sex, race, educational level,
health insurance, BMI, ABI, total cholesterol,
heart disease and stroke, pulmonary disease,
diabetes, arthritis, and log CRP
*Values are expressed as means (SD) for unadjusted analyses and adjusted means for adjusted functional measures.
Adjusting for confounders, aspirin use was associated with
faster 4-meter walking speed compared with no aspirin use in
patients with ABI ⬍0.90 (0.89 versus 0.85 m/s, P⫽0.044).
There were no other significant associations between aspirin use,
␤-blocker use, ACE inhibitor use, or vasodilator use and
lower-extremity functioning among participants with ABI
⬍0.90, participants with ABI 0.90 to 1.49, or all participants
(data not shown).
Adjusting for all previous confounders plus CRP, the association between statin use and better lower-extremity functioning
was attenuated among all participants for 6-minute walk distance
and 4-meter walking velocity (Table 2). The significant relationship between statin use and higher summary performance score
was maintained and not attenuated. Even after adjustment for
CRP, relations between statin use and 4-meter walking velocity
as well as the summary performance score remained highly
statistically significant (Table 2).
Discussion
Among persons with and without PAD, statin users had better
performance on objective measures of leg functioning than
statin nonusers. Statin users had several characteristics associated with greater impairment in functioning compared with
nonusers, including a higher prevalence of heart disease and
stroke and a higher proportion of participants with ABI
⬍0.90 compared with nonusers. Nonetheless, statin use was
associated with better functioning compared with nonuse
after adjustment for these and other confounders.
A large body of literature has established that statins have
favorable actions on atherosclerosis and vascular properties
other than those attributed to cholesterol lowering.1– 6,22,23 Statins
increase production of nitric oxide in the endothelium, which has
local vasodilatory properties in addition to antithrombogenic,
antiproliferative, and leukocyte-adhesion inhibiting effects.22,23
Other mechanisms by which statins favorably influence atherosclerosis include enhancement of endothelium-dependent relaxation,3 inhibition of platelet function,5 and inhibition of
endothelin-1, a potent vasoconstrictor and mitogen.4 Therefore,
it is biologically plausible that statins might improve lowerextremity functioning in PAD by retarding the deleterious
effects of atherosclerosis on leg arteries. Furthermore, the
association between statin use and functional performance was
attenuated slightly after adding CRP to the fully adjusted model,
suggesting that reduction of vascular inflammation may be one
mechanism by which statins are associated with better functioning. Statin-associated reduction of inflammatory cytokines could
improve blood flow, regress atherosclerosis, or improve endorgan function (such as skeletal muscle).24
We cannot rule out the possibility that positive associations
between statin use and functioning are attributable to unmeasured confounders associated with better medical care, healthier
lifestyle, or higher socioeconomic status that we could not fully
adjust for in our analyses. To test this possibility, we studied
relations between aspirin, ␤-blocker, and ACE inhibitor use with
functioning. ␤-blocker use does not influence treadmill-walking
performance in patients with PAD but could reflect better
medical care.25 We also studied relationships between vasodila-
McDermott et al
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tor use and lower-extremity functioning, because vasodilatation
could theoretically improve leg functioning in PAD. We found
no consistent associations between use of these drugs and
functioning, suggesting that the relation between statin use and
better leg functioning is not a consequence of better medical care
associated with statin use. Although a positive relation between
statin dose and better leg functioning would strengthen our
findings, we did not have information on statin dose. We also did
not have information on duration of statin use. However, recent
data indicate that the antiinflammatory actions of statins are
immediate,26 suggesting that the relation between statin use and
leg functioning may not be affected by statin use duration.
To our knowledge, only one clinical trial has evaluated the
relationship between statins and PAD outcomes. The Scandinavian Simvastatin Survival Study (4S) demonstrated that subjects
randomized to simvastatin had a 38% reduction in new or
worsening claudication compared with subjects randomized to
placebo over a median follow-up of 5.4 years (P⫽0.008).27 We
know of no previous studies relating statin use to lowerextremity functioning.
The favorable association between statin use and functioning
was also observed in participants with ABI 0.90 to 1.49. This
beneficial association may relate to a favorable influence of
statins on subclinical lower-extremity atherosclerosis. Previous
work shows that non-PAD patients with ABI values of 0.90 to
1.10 have poorer functioning than patients with ABI values of
1.1 to 1.50, suggesting that subclinical lower-extremity atherosclerosis impairs leg functioning.7 Better functioning in the
non-PAD group taking statins may additionally relate to beneficial effects of statins on inflammatory-mediated impairments
in skeletal muscle function.24
In conclusion, statin-associated benefits on endothelial function and vascular inflammation may improve leg functioning in
patients with and without PAD. Confirmation of this finding
elsewhere, as well as additional study of the mechanisms
pertaining to the association between statin use and superior
functioning, are indicated. It will also be important to determine
whether deliberate statin use improves functioning in patients
with optimal cholesterol levels.
Acknowledgments
Supported by grants No. R01-HL64739 and R01-HL58099 from the
National Heart Lung and Blood Institute and by No. RR-00048 from
the National Center for Research Resources, National Institutes of
Health. Dr McDermott is recipient of an Established Investigator
Award from the American Heart Association. The authors thank the
study participants and their physicians for their time and effort on
behalf of the study.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
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Statin Use and Leg Functioning in Patients With and Without Lower-Extremity
Peripheral Arterial Disease
Mary McGrae McDermott, Jack M. Guralnik, Philip Greenland, William H. Pearce, Michael H.
Criqui, Kiang Liu, Lloyd Taylor, Cheeling Chan, Leena Sharma, Joseph R. Schneider, Paul M
Ridker, David Green and Maureen Quann
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Circulation. 2003;107:757-761; originally published online January 27, 2003;
doi: 10.1161/01.CIR.0000050380.64025.07
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