Fibrinogen: Associations with cardiovascular

events in an outpatient clinic

Monica Acevedo, MD, JoAnne Micale Foody, MD, Gregory L. Pearce, MS, and Dennis L. Sprecher, MD Cleveland, Ohio

Background Fibrinogen, known to influence the coagulation process, is an independent risk factor for coronary artery
disease (CAD). However, its association with myocardial infarction (MI) and its predictive potential for short-term mortality,
in an ongoing clinical practice, has not been characterized.
Objectives In a high-risk outpatient practice we sought to demonstrate whether baseline fibrinogen levels related to MI
rather than CAD alone, and whether baseline serum fibrinogen levels predicted mortality over a short-term follow-up.
Methods and Results From a total of 2126 patients with baseline fibrinogen measurements (mean age, 56 ± 12
years, 35% female), 1187 patients with CAD (n = 606 with MI) and 939 patients without CAD were evaluated in an active
preventive cardiology unit of a large city hospital. Logistic regression models were used to determine the association of fi-
brinogen with differing CAD presentations. Fibrinogen quartile showed a significant correlation with CAD both univariately
and after adjustment for Framingham risk score (odds ratio [OR] = 1.22, P < .001). Fibrinogen levels were significantly asso-
ciated with the presence of CAD and history of MI (adjusted OR = 1.25, P = .001). Fibrinogen did not show a significant
association to CAD when MI was not considered in the analysis (OR = 1.01, P = .82). In this same clinical cohort, after a
mean follow-up of 24 ± 13 months, 41 patients had died. Consistent with the observed association with MI, fibrinogen quar-
tile showed a graded independent relation to mortality in a cohort of both men and women (hazard ratio = 1.81, P < .001).
Conclusions In the clinical setting of an outpatient clinic, fibrinogen was directly associated with the presence of MI
and was revealed to be an independent short-term predictor of mortality. (Am Heart J 2002;143:277-82.)

Over the past decade coagulation factors, in particular
fibrinogen, have been identified as independent risk fac-
tors for coronary artery disease (CAD).1-10 Fibrinogen
plays an important role in thrombosis through platelet
aggregation, a major physiologic pathway for the clini-
cal onset of ischemia and myocardial infarction (MI).11-
13 Yet, there is also evidence that fibrinogen is involved
in the progression of atherosclerotic disease,14 outside
of acute coronary syndromes.
These findings are supported by large epidemiologic
studies that have revealed significant associations
between plasma fibrinogen levels at entry and subse-
quent cardiovascular events (including fatal and nonfatal
MI and stroke3,4,6,15-17 and the extent of coronary ather-
osclerosis.18-20
We chose to assess the predictive potential of measur-
ing serum fibrinogen levels in participants of an ongo-
ing outpatient clinical prevention program. First, we
expected fibrinogen to primarily relate to thrombotic
From the Department of Cardiology, Section of Preventive Cardiology and Cardiac
Rehabilitation, The Cleveland Clinic Foundation.
Submitted March 6, 2001; accepted Aug 16, 2001.
Reprint requests: Dennis L. Sprecher, MD, Section Head, Preventive Cardiology and
Rehabilitation, Department of Cardiology, C51, The Cleveland Clinic Foundation,
9500 Euclid Ave, Cleveland, Ohio 44195.
E-mail: sprechd@cesmtp.ccf.org
Copyright © 2002 by Mosby, Inc.
0002-8703/2002/$35.00 + 0 4/1/119766
doi:10.1067/mhj.2002.119766
events, that is, to demonstrate an association with MI
compared with CAD alone in the cross-sectional setting.
Second, if elevated fibrinogen levels enhanced the prob-
ability of MI, we would anticipate an association with
short-term mortality, particularly in the high-risk setting,
for both primary and secondary prevention patients.
Methods
All men and women with a measured fibrinogen at the first
consult to our Preventive Cardiology Unit at the Cleveland
Clinic Foundation between January 1996 and August 2000 (n =
2126) were selected. More than 70% of our patients are
referred from other cardiovascular services in the same institu-
tion, whereas nearly 30% are referred from outside institutions
or physicians. Patients are routinely assessed for traditional car-
diovascular risk factors: age, sex, total cholesterol (TC), low-
density lipoprotein-cholesterol (LDL-C), high-density lipopro-
tein-cholesterol (HDL-C), triglycerides (TG), hypertension,
diabetes, smoking, and family history for CAD, and several
nontraditional risk factors including fibrinogen. Demographic,
general medical, and cardiovascular data (including updated
list of medications) were obtained by patient self-report
through a questionnaire and were corroborated with the main
clinical charts by a clinician (registered nurse or physician
assistant) and were then recorded in an electronic database.
Patients
From the overall cohort, we then selected all the patients
with known CAD referred to the prevention clinic. CAD was

278 Acevedo et al
diagnosed in the presence of (1) documented MI, unstable
angina, and/or stable angina, and/or (2) a coronary angiogra-
phy indicating a stenosis >50% in at least 1 major coronary
artery, and/or (3) coronary artery bypass grafting, and/or (4) a
positive noninvasive cardiac test. Self-reported cardiovascular
disease history was validated with the Cleveland Clinic Cardio-
vascular Interventional Registry and main clinical charts in
institutional patients, and from a medical chart review or
physician information for the patients referred from other
institutions or physicians.
No patient was referred exclusively to the clinic because of
an elevated fibrinogen level.
On September 1, 2000, the vital status of these individuals
was assessed by a search in the National Social Security
Administration death index database.
Data Collection
All the patients on their first visit to the clinic under-
went a clinical and physical examination that included
anthropometry (height, weight, waist to hip ratio),
blood pressure, and a fasting blood draw for a complete
lipid profile, glucose, creatinine, and fibrinogen.
Patients were classified as either never or ever smokers.
Hypertension was defined when the patient declared a
history of high blood pressure (physician labeled) and a
resting blood pressure ≥140/90, or the use of antihyper-
tensive medications. Diabetes was diagnosed predomi-
nantly if the patient was taking an oral hypoglycemic
agent or insulin, but in some few instances, when the
patient reported a history of diabetes.
Laboratory Testing
Fasting TC, HDL-C, LDL-C, and TG were taken at the same
time fibrinogen was measured in all the patients. TC, HDL-C,
LDL-C, and TG were measured in serum after a 12-hour fast
and analyzed by enzymatic assays (Hitachi Analyzer,
Boehringer Mannheim).21 When TG values were >400 mg/dL,
lipid values were analyzed by immunoprecipitation.
Fibrinogen levels were measured on citrated plasma by modi-
fication of the Clauss method with a Sysmex CA-6000 Fibrin-
ometer.22 The mean value in our laboratory is 300 mg/dL, with
a reference range of 200 to 400 mg/dL; the coefficient of varia-
tion is <4%. Fibrinogen levels in the CAD population were mea-
sured an average of 37 months after the most recent qualifying
cardiac event or procedure.
All blood samples were analyzed at the Cleveland Clinic
Foundation Clinical Laboratory and processed immediately.
Statistics
Logistic regression models were formulated to assess the rela-
tion between fibrinogen and (1) CAD, (2) CAD without MI, and
(3) CAD with previous MI (PROC LOGISTIC, SAS Institute, Cary,
NC). Odds ratios (OR) were constructed to estimate the adjusted
risk for each quartile increase in fibrinogen. Cox proportional
hazard regression models were used to assess the relations
between fibrinogen quartiles (<288, 289 to 300, 331 to 381,
>382 mg/dL) and survival time, with hazard ratios (HR) used to
estimate mortality risk. Ninety-five percent confidence intervals
(CI) were constructed for both OR and HR. Risk adjustments
American Heart Journal
February 2002
were made using Framingham Risk Scores, which incorporate
the traditional risk factors of age, sex, LDL-C, HDL-C, blood pres-
sure, diabetes, and smoking.23 This method was chosen to pre-
vent overmodeling in the longitudinal setting, because the event
rate (n = 41) was too low to simultaneously adjust for traditional
risks individually. Fibrinogen was divided into quartiles to facili-
tate its use as a clinical tool and because the fibrinogen distribu-
tion was not normal. Models using natural logarithm transforma-
tions were developed also to corroborate the conclusions from
the quartile-based models.
Results
Table I presents a detailed description of the base-
line demographic, clinical, and laboratory data for the
study population. From the overall population of 2126
patients with baseline fibrinogen measurements, 1187
(56%) had known CAD. Of these, 606 (51%) had a
documented previous MI, and 581 (49%) had CAD
exclusive of previous MI. Patients with CAD had
higher fibrinogen levels than patients without CAD
(341 vs 315 mg/dL, P < .001) (Table I). Within the
CAD group, patients with a history of MI had higher
fibrinogen levels than those without MI (344 vs 336
mg/dL, P = .002).
Fibrinogen exhibited a significant relationship to age (P
< .001), sex (female) (P < .001), LDL-C (P < .001), systolic
blood pressure (P < .001), history of diabetes (P < .001),
and current smoking status (P < .001). A marginally nega-
tive significance was found for HDL-C (P = .07). However,
the overall logistic regression model showed a significant
positive correlation between fibrinogen quartile and CAD
both univariately (OR = 1.32, P < .001) and adjusted for
Framingham risk score (OR = 1.22, P < .001) (Table II).
The differential effects of fibrinogen on the differing
CAD presentations (ie, CAD with and without MI) were
subsequently assessed. For the MI-based model the
adjusted OR for fibrinogen quartile was significant (OR
= 1.25; P < .001) (Table II). However, in the model for
CAD without MI, the adjusted OR for fibrinogen quar-
tile was no longer significant (OR = 1.01; P = .82)
(Table II). The same relations between fibrinogen and
events were observed when men and women were ana-
lyzed separately. The breakdown of rates by sex is
shown for CAD and MI (Figure 1, A and B).
After a mean follow-up of 24 ± 13 months, 41 (1.9%)
patients in the overall cohort had died: 33 in the CAD
group and 8 in the non-CAD population. A graded rela-
tion between fibrinogen levels and mortality was found
in the overall population: 3 of 536 (0.6%), 5 of 540
(0.9%), 9 of 520 (1.7%), and 24 of 530 (4.5%) deaths,
respectively, in each successive fibrinogen quartile (Fig-
ure 2). Plasma fibrinogen showed a strong and signifi-
cant unadjusted (HR 2.01; CI = 1.43-2.84, P < .001) and
risk-adjusted relationship (HR = 1.81, CI = 1.27-2.58, P
= .001) to mortality in the overall cohort.
Logistic regression models were also developed using
American Heart Journal
Volume 143, Number 2 Acevedo et al 279

Table I. Presentation of baseline demographic, clinical characteristics, and laboratory data for the study population and by CAD status
Overall Non-CAD CAD

n 2126 939 1187

Age (y) 56 ± 12 51 ± 12 60 ± 11*
Sex (female) (%) 740 (35) 441 (47) 299 (25)*
Body mass index 28.8 ± 5.3 28.5 ± 5.5 29 ± 5.2*
TC (mg/dL) 227 ± 75 250 ± 80 209 ± 65*
TG (mg/dL) 176 (118-271) 195 (123-324) 161 (114-245)*
HDL-C (mg/dL) 45 ± 14 47 ± 16 43 ± 12*
LDL-C (mg/dL) 130 ± 53 142 + 60 121 ± 46*
Systolic BP (mm Hg) 131 ± 20 130 ± 19 131 ± 21
History of diabetes (%) 391 (18) 118 (13) 273 (23)*
Current smoker (%) 206 (10) 108 (12) 98 (8)*
Statins medications (entry) (%) 669 (31) 163 (17) 206 (43)*
BP medications (entry) (%) 1187 (56) 281 (30) 906 (76)*
Framingham risk score 5.4 ± 4.2 4.6 ± 4.6 6.1 ± 3.7*
Death (%) 41 (1.9) 8 (0.9) 33 (2.8)*
Fibrinogen (mg/dL) 330 (288-381) 315 (280-363) 341 (295-394)
Fibrinogen and triglycerides were characterized by median and interquartile range because they were not normally distributed. Other continuous measures are depicted by
mean (±SD), and categorical measures are depicted by number (percent).
CAD, Coronary artery disease; MI, myocardial infarction; TC, total cholesterol; TG, triglycerides; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cho-
lesterol; BP, blood pressure.
*P ≤ .01 for difference between CAD and non-CAD.

natural logarithmic transformations for fibrinogen to Figure 1

corroborate the conclusions derived from the quartile-
based models. The OR for logarithm of fibrinogen was
2.88 (P = < .001) in the CAD model, 3.40 (P = < .001)
in the previous MI model, and 0.98 (P = .94) in the
CAD without MI model. The proportional hazard
regression produced an HR for mortality of 19.8 by fi-
brinogen quartile (P < .001).

Discussion
In the novel setting of an ongoing outpatient clinical
operation, fibrinogen proved to be directly associated
with the presence of CAD, particularly MI, even after
adjustment was done for traditional risk factors. As evi-
dence of this cross-sectional association, fibrinogen was A
found to be an independent predictor of all-cause mor-
tality in both men and women on longitudinal short-
term follow-up.
Over the past decade fibrinogen has been identified
as an independent risk factor for CAD in several large
prospective studies.2-10 Meade et al2 first described
fibrinogen as a risk factor for CAD and mortality in
1980, when the preliminary results of the Northwick
Park Heart Study were published. In this study of 1511
men, high fibrinogen levels were associated with an
84% increased risk for fatal or nonfatal cardiovascular
events.6 Several other prospective and cross-sectional
studies have also revealed that fibrinogen levels are
associated with subsequent cardiovascular B
events.3,4,16,17,24 In a more recent meta-analysis, Prevalence of coronary artery disease (CAD) (A) and myocar-
Maresca et al25 further corroborated the data pre- dial infarction (MI) (B) by sex for each fibrinogen quartile.
sented by Ernst and Resch26 in 1993. They showed

280 Acevedo et al
Figure 2
Mortality rate by fibrinogen quartile.
that the risk of a cardiovascular event in subjects in
the higher fibrinogen tertile was almost twice the risk
in those in the lower tertile (OR = 1.99, P < .05), and
that higher fibrinogen levels implied an increased car-
diovascular risk in the general population and
patients with prevalent CAD.
In our high-risk cardiovascular population, we have
corroborated the relation between fibrinogen and the
presence of clinical CAD,10,27,28 with equivalent find-
ings in the subgroup noted to have a history of MI.
There was a tendency for disease prevalence to
increase with fibrinogen quartile in both comparisons.
However, this association was not observed when MI
was not considered in the CAD analysis. This distin-
guishing characteristic was addressed partly by the
PLAT study,29 where the relation between hemostatic
function and atherothrombotic ischemic events in
patients with different presentations of vascular disease
was investigated prospectively. Fibrinogen levels pre-
dicted thrombotic events in patients with a history of
MI but not in patients with chronic angina. This finding
suggests an association of fibrinogen with acute CAD
presentations, parallel to our own findings, and there-
fore implicates a relation to thrombotic events. If this
association were causal, we might expect a subsequent
influence on mortality.
Although our sample of events is small, the finding of
a positive association between fibrinogen levels and
mortality, in a population in which fibrinogen elevation
is already implicated as related to MI, is particularly
compelling. Our current analyses specifically focused
on mortality as the primary end point. The strength of
the association between fibrinogen and mortality in our
overall cohort was similar (adjusted HR = 1.81; P =
.001), if not stronger, than previously reported in pri-
mary epidemiologic studies. The Northwick Park Heart
American Heart Journal
February 2002
Table II. Unadjusted and adjusted risks associated with each
increase in fibrinogen quartile
Odds/hazard
ratio 95% CI P value
Unadjusted
CAD 1.32 1.22-1.42 <.001
CAD without MI 1.06 0.98-1.16 .16
MI 1.31 1.20-1.43 <.001
Adjusted*
CAD 1.22 1.12-1.32 <.001
CAD without MI 1.01 0.92-1.11 .82
MI 1.25 1.15-1.37 <.001
CAD, Coronary artery disease; CAD without MI, coronary artery disease without
myocardial infarction; MI, myocardial infarction; CI, confidence intervals.
*Adjusted for Framingham Risk Score.
Study,6 for example, demonstrated a standardized
regression effect for fibrinogen tertile of 1.25 for all-
cause mortality in men (P = .002), whereas the Athero-
sclerotic Risk in Communities Study (ARIC)15 showed a
relative risk of 1.3 for men and 1.37 for women (P <
.05). Martin et al,30 Burr et al,31 and Benderly et al32
confirmed such associations in the few reported sec-
ondary prevention studies that focused on mortality.
Finally, the results from our study not only support the
value of fibrinogen in men but also in women, in whom
fibrinogen previously has been found to be both
related15 and also unrelated16,17 to mortality outcomes.
The clinical importance of our findings relates to the
cardiovascular predictive potential of measuring fi-
brinogen in the common clinical outpatient setting.
Such data does not, however, help characterize the
value of blocking fibrinogen-induced platelet aggrega-
tion or the benefit of reducing fibrinogen levels. We are
aware that lowering fibrinogen serum levels result from
smoking cessation and exercise, and that fibrates (ie,
bezafibrate or fenofibrate) along with ticlopidine (a
platelet inhibitor) have consistently demonstrated
reductions in fibrinogen concentrations.33,34 Although
short- and long-term aspirin use has not shown signifi-
cant reductions in fibrinogen levels,35-37 it may be spec-
ulated that aspirin could inhibit the fibrinogen effect on
platelets. In summary, there is no clinical evidence to
target fibrinogen reduction or inhibition; however,
high fibrinogen levels may particularly compel the clini-
cian to choose a fibrate for lipid disorders, emphasize
exercise, or administer aspirin given the otherwise
known value of these modalities for cardiovascular
health.
There are several limitations to our study conclu-
sions. (1) We presented both cross-sectional and longi-
tudinal data in this study, and as such, in the analyses,
biases can be introduced that are inherent to a non-
randomized trial. (2) Our population corresponds to a
American Heart Journal
Volume 143, Number 2
high-risk cardiovascular population and therefore has
an increased amount of traditional risk. Yet, all of our
results were adjusted for Framingham risk score with
similar outcomes. (3) We did not adjust our results for
other conditions (ie, menopause, obesity, activity level)
or medications (ie, oral contraceptives, fibrates) that
could have influenced fibrinogen levels. Although this
might have influenced the results drawn from cross-
sectional data, it should have primarily weakened the
positive conclusions observed in the longitudinal exam-
ination. (4) We did not measure other markers of
inflammation, for example, C-reactive protein. Al-
though correlations between fibrinogen and C-reactive
protein25,38-40 have been recorded, the association
between fibrinogen levels and coronary events has
remained statistically significant even after adjustment
for C-reactive protein serum concentrations.20,40 (5)
Finally, study subject vital status was assessed only
through the Social Security National Death Index. Thus
no data on specific causes of death are available.
In conclusion, in this first analysis from an ongoing
outpatient clinic, fibrinogen proved to be directly associ-
ated with the presence of MI and, as anticipated, to be
an independent predictor of all-cause mortality in the
same cohort. This finding strengthens the predictive role
of fibrinogen in both men and women and advances our
understanding of this hemostatic factor in cardiovascular
outcomes. Fibrinogen may be a reasonable prognostic
tool for short-term follow-up in a clinical program.
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