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Incident Thromboembolism in the Aorta and the Renal, Mesenteric, Pelvic, and Extremity Arteries After Discharge From the Hospital With a Diagnosis of Atrial Fibrillation
Lars Frost, MD, PhD;
Gerda Engholm, MS;
Søren Johnsen, MD;
Henrik Møller, MS;
Eskild W. Henneberg, MD;
Steen Husted, MD, PhD
Arch Intern Med. 2001;161:272-276.
ABSTRACT
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Background The impact of atrial fibrillation (AF) on risk of peripheral arterial
thromboembolism is unknown.
Methods We analyzed the risk of thromboembolism (embolus and/or thrombosis)
in the aorta and the renal, mesenteric, pelvic, and extremity arteries in
a cohort of patients discharged from the hospital with an incident diagnosis
of AF relative to the risk of thromboembolism in these vessels in the Danish
population. In a random sample of half of the Danish population, 14 917
men and 14 945 women aged 50 to 89 years were identified in the Danish
National Hospital Discharge Register with a diagnosis of AF from January 1,
1980, through December 31, 1993. Patients were followed up from diagnosis
of AF in the Danish National Hospital Discharge Register and the Causes of
Death Register until the first diagnosis of a thromboembolic event, death,
or the end of 1993. Risk of a thromboembolic event relative to the risk in
the Danish population was analyzed by means of Poisson regression modeling.
Results Patients with a hospital diagnosis of AF had an increased risk of thromboembolic
events in the aorta and the renal, mesenteric, pelvic, and extremity arteries
(relative risk, 4.0 [95% confidence interval, 3.5-4.6] in men; and relative
risk, 5.7 [95% confidence interval, 5.1-6.3] in women) compared with the Danish
population.
Conclusion A hospital diagnosis of AF is an important risk factor for peripheral
arterial thromboembolic complications.
INTRODUCTION
IT IS WELL documented that patients with atrial fibrillation (AF) have
an increased risk of cerebrovascular thromboembolism.1, 2, 3, 4, 5, 6, 7, 8, 9, 10
The incidence of peripheral arterial thromboembolic events (ie, thromboembolic
events outside the cerebral and coronary artery systems) in patients with
AF is lower than the incidence of stroke.11
The main reason for this may be that most of the cerebral arteries are functional
end arteries, whereas occlusion of many other arteries may not lead to clinical
manifestations because of protection from collateral circulation. Clinical
articles on series of patients with peripheral thromboembolism report that
30% to 80% of patients with acute peripheral thromboembolic events have AF.12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37
This indicates that AF is the most important risk factor for peripheral thromboembolism.
We have found no reports on estimates of risk of peripheral arterial thromboembolism
in patients with AF. Therefore, the purpose of this article was to analyze
the risk of thromboembolism in the aorta and the renal, mesenteric, pelvic,
and extremity arteries in patients discharged from the hospital with an incident
diagnosis of AF relative to the risk of thromboembolism in the same vascular
beds in the Danish population.
MATERIALS AND METHODS
STUDY POPULATION
The general health and hospital care systems in Denmark are noncharge
and nonprofit systems that are financed through taxes. The cohort of patients
with AF was found within a nearly 50% random sample (all persons with 1 of
15 randomly selected birthdays a month) from the Danish population. Patients
were included in the cohort if they were discharged from the hospital from
January 1, 1980, through December 31, 1993, with an incident diagnosis of
AF and had no history or presence of a peripheral thromboembolism (including
emboli as well as thromboses) in the Danish National Hospital Discharge Register.
Registrations with modification codes not found or under observation for were excluded. Patients whose conditions
solely were diagnosed in outpatient clinics were not included in the present
cohort. To avoid inclusion of prevalent cases, patients who had received a
diagnosis of AF or peripheral thromboembolism in the Danish National Discharge
Register from January 1, 1977, through December 31, 1979, were excluded. The
month and year of the first registration (ie, incidence) of AF was registered,
along with registration of age and sex. Previous (from 1977) or simultaneous
diagnosis in the Danish National Hospital Discharge Register of diseases disposing
to AF38, 39, 40 or
peripheral thromboembolism were recorded, eg, hypertension; diabetes; ischemic
heart disease, with or without acute myocardial infarction; congestive heart
failure; stroke; mitral valve disease; aortic valve disease; and peripheral
atherosclerosis.
Data on the incidence of a hospital diagnosis of AF in the Danish population
from January 1, 1980, through December 31, 1993, have been published elsewhere41 together with outcome data, such as total and cardiovascular
mortality41 and stroke.10
FOLLOW-UP
Patients were followed up in the Danish National Hospital Discharge
Register and the Causes of Death Register from diagnosis of AF until the first
diagnosis of a thromboembolic event (ie, embolus or thrombosis), death, or
the end of 1993. Follow-up used the personal identification number, a 10-digit
code that is a unique identification of every person with an address in Denmark
at any time since April 1968. Follow-up ended at the end of 1993 because of
a change in the World Health Organization International Classification of
Diseases (ICD) that occurred in Denmark in 1994. Diseases were coded by the
medical staff in the discharging hospital according to International Classification of Diseases, Eighth Revision (ICD-8) codes.42 Cause of death was coded
by the Danish National Board of Health according to World Health Organization
standards on the basis of causes of death noted in death certificates, which
were filled in by physicians in the hospital, in general practice, or in forensic
medicine.
The definitions of diseases and causes of death by ICD-8 codes for the present analysis are available from the authors.
Persons who died within the same month as the incident AF diagnosis
(n = 2580) were excluded from the analysis.
STATISTICAL METHODS
Sex-, age- and calendar-year–specific incidence rates of peripheral
thromboembolism in the population were calculated by dividing the number of
incident cases in the population sample by the corresponding person-years
in the 50% sample from the Danish population. Person-years at risk for a peripheral
arterial thromboembolism for the AF cohort was calculated for each sex in
5-year age groups and for 3 calendar periods: 1980-1984, 1985-1989, and 1990-1993.
The observed number of peripheral thromboembolic events was compared with
that expected for the cohort. The expected number of peripheral thromboembolic
events was calculated by multiplying person-years at risk by the corresponding
sex-, age-, and calendar-year–specific incident peripheral thromboembolic
event rates in the Danish population. The crude relative risk (RR) (the ratio
between the observed and expected number of outcomes) and the excess number
and excess risk (the difference between the observed and expected number of
outcomes, and the difference divided by the person-years at risk, respectively)
were calculated for each 10-year age group in men and women. A more consistent
variation in RR than in excess risk was seen across ages and sex. Therefore,
analysis of risk variation has been used, giving a multiplicative rather than
an additive risk model.
The RR of peripheral thromboembolism, defined
as the observed divided by expected number of peripheral thromboembolic events,
was analyzed separately for men and women by means of Poisson regression models.43 In such log-linear or multiplicative regression models,
the observed number is considered to be Poisson-distributed. The logarithm
of the expected number of peripheral thromboembolic events was used as an
offset variable (ie, a constant in the log-linear regression model), and the
covariates (ie, age and calendar time at AF diagnosis, time since diagnosis,
and status of earlier or concomitant diseases) were multiplicative factors
in the model. For each of the covariates (except age), 1 of the categories
was chosen as the reference, and the reported estimated values for the other
categories can be interpreted as RRs compared with this reference category,
standardized for the other factors in the model. For the covariates describing
previous diseases, the group with no previous disease was the reference category.
This illustrates relative changes in risk for the cohort relative to the population
rates. The interpretation of an estimated age value is the RR for the cohort
at the reference category of covariates compared with the Danish population
for the specific age group.
Poisson regression models were fitted using PROC GENMOD in SAS statistical
software (SAS Version 6.12; SAS Institute Inc, Cary, NC).
RESULTS
DEMOGRAPHIC AND CLINICAL DATA
The cohort of patients with an incident hospital discharge diagnosis
of AF and no previous discharge diagnosis of peripheral arterial thromboembolism
from January 1, 1980, through December 31, 1993, consisted of 29 862
individuals (14 917 men and 14 945 women) aged 50 to 89 years.
The proportions of previous or concomitant hospital discharge diagnoses
of hypertension; diabetes; ischemic heart disease, with or without myocardial
infarction; congestive heart failure; stroke; mitral valve disease; aortic
valve disease; and peripheral atherosclerosis are shown in Table 1.
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Table 1. Demographic and Clinical Data for Persons in the Danish Atrial
Fibrillation Cohort, 1980-1993*
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For men in the AF cohort, the crude peripheral thromboembolism rates
in the age intervals 50 to 59, 60 to 69, 70 to 79, and 80 to 89 years were
3, 4, 6, and 4 per 1000 person-years, respectively. In women, the rates in
the same age intervals were 2, 5, 8, and 10 per 1000 person-years, respectively.
Six hundred twenty-one persons had events of peripheral arterial thromboembolism.
The distribution of events in the body were: 7% in the aorta, 2% in the renal
artery, 29% in the mesenteric arteries, 9% in the pelvic arteries, and 61%
in the upper and lower extremities. Some patients had events in more than
1 site at the same time.
In men and women, the observed vs expected numbers of peripheral thromboembolic
events were 232 vs 57.3 and 389 vs 68.6 during 48 660.0 and 51 007.8
years at risk, respectively (Table 2).
Thus, the crude RR of a peripheral thromboembolic event was 4.0 (95% confidence
interval, 3.5-4.6) for men and 5.7 (95% confidence interval, 5.1-6.3) for
women compared with the Danish population. Nearly half of the excess events
occurred in patients aged 70 to 79 years (Table 2).
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Table 2. Crude Risk Measures of Thromboembolic Events for Persons in
the Danish Atrial Fibrillation Cohort, 1980-1993*
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RISK FACTORS FOR PERIPHERAL ARTERIAL THROMBOEMBOLISM
Risk factors for peripheral arterial thromboembolism in the AF cohort
are shown in Table 3. At the reference
category for the other risk factors (ie, the second year after AF diagnosis
and no history or presence of concomitant diseases), patients aged 60 to 69
years had a 4.0-fold (men) and 6.8-fold (women) increase in RR of peripheral
thromboembolism compared with the Danish population. The RR of thromboembolism
diminished with increasing age. Men and women aged 80 to 89 years had a 1.9-
and 3.2-fold increase in relative thromboembolic risk, respectively.
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Table 3. Risk Factors for Thromboembolism for Persons in the Atrial
Fibrillation Cohort (1980-1993) vs the Danish Population*
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The highest risk of peripheral arterial thromboembolism was seen during
the first year after incident AF diagnosis; thereafter, the thromboembolic
risk declined (Table 3).
In both men and women, a higher RR of peripheral thromboembolism was
present in patients with diagnoses of peripheral atherosclerosis, acute myocardial
infarction, and stroke. In men, a higher thromboembolic risk was also present
in diabetic patients with AF. In women, a higher thromboembolic risk was also
seen in patients with hypertension or congestive heart failure.
COMMENT
We have documented that a hospital diagnosis of AF is associated with
a 4.0-fold (men) and 5.7-fold (women) increase in RR of incident peripheral
arterial thromboembolism compared with the Danish population.
Peripheral atherosclerosis was a significant risk factor for thromboembolism
in both men and women. There may be more than 1 possible pathophysiological
mechanism. First, distant lodgment of embolic material may take place at a
distally located atherosclerotic plaque formation, causing total obstruction
of the blood flow. Second, the embolic material may originate from the fibrillating
atrium or from a ruptured plaque proximal to the site of the acute occlusion.
Third, localized thrombus formation may have caused some cases of thromboembolism.
Fourth, AF per se activates the coagulation system44, 45, 46, 47;
this may facilitate local thrombus formation in case of a plaque rupture.
A history of myocardial infarction was associated with a moderately
increased risk of peripheral thromboembolism in men and women. The mechanism
may be formation of a mural thrombus in the infarction zone with subsequent
embolization, or the myocardial infarction may be caused by embolization from
the fibrillating atrium to a coronary artery and thus indicates a risk of
embolization from the fibrillating atrium. Finally, if the myocardial infarction
was caused by plaque rupture, the patient has demonstrated a capability of
plaque rupture and local thrombus formation. This capability may also be present
in the peripheral vascular system.
A history of stroke was a risk factor for thromboembolism in both men
and women. However, a history of stroke did not attain statistical significance
in women. We believe that if we had had a larger cohort of patients with AF,
a history of stroke also would have shown statistical significance in women.
Diabetes was a significant risk factor for peripheral thromboembolism
in men but not in women. The ICD-8 coding system
does not differentiate between type 1 and type 2 diabetes mellitus before
1986. One possible explanation for the significance of diabetes in men may
be a preponderance of type 2 diabetes in men, since type 2 diabetes is associated
with more widespread atherosclerosis than type 1. This is in accord with men
having a higher incidence rate of type 2 diabetes than women in Denmark.
Hypertension and heart failure were risk factors for a thromboembolic
event in women but not in men. The present series included a limited number
of thromboembolic events. It is possible that the dissimilarities observed
in the risk factors for thromboembolic events in men and women originated
from significance by chance, or that misclassification of hypertension and
congestive heart failure may have introduced bias. However, we have no reason
to believe that misclassification of hypertension and congestive heart failure
should depend on sex. It is, therefore, most likely that the observed differences
between men and women derive from residual confounding. We had no information
on potentially confounding factors, such as the type of AF (ie, paroxysmal,
persistent, or permanent), family history of AF, social class, exercise habits,
smoking status, cholesterol level, body mass index, severity of comorbidity,
and medication, including coumarin therapy.
The ICD-8 coding does not differentiate between
an embolus and a thrombosis as the cause of an acute arterial occlusion; however,
this is not a serious limitation. First, 81% of acute peripheral arterial
occlusions are embolic.23 Second, in the presence
of AF, it can be assumed that an even higher proportion of acute vascular
occlusion is caused by embolization. Third, in surgery or during autopsy,
it often may be impossible to differentiate between embolization and/or thrombus
formation, especially when differentiating between acute and acute on chronic
limb ischemia.48
Randomized trials have documented that coumarin therapy reduces the
risk of stroke in patients with AF by 68%.49
A randomized trial to demonstrate the effect of coumarin therapy on risk of
peripheral thromboembolism in patients with AF will never be performed, because
it would be deemed unethical to randomize patients with AF to placebo treatment.
We believe that coumarin therapy is effective in preventing peripheral
arterial thromboembolism in patients with AF. Indirect evidence for this comes
from the fact that heart valve disease was not associated with an increased
risk of peripheral thromboembolism in the present cohort. This may be caused
by the widespread use of coumarin derivatives in patients with heart valve
disease with or without AF.
Besides an increased risk of thromboembolic cerebrovascular events,
patients with AF also have an increased risk of peripheral arterial embolism.
We advocate that this also should be taken into account when considering anticoagulation
therapy in patients with AF.
AUTHOR INFORMATION
Accepted for publication June 30, 2000.
Presented at the 49th Annual Scientific Session of the American College
of Cardiology, Anaheim, Calif, March 12, 2000.
From the Department of Cardiology, Amtssygehuset, Aarhus University
Hospital (Drs Frost, Johnsen, and Husted), and Department of Clinical Epidemiology,
Aarhus University Hospital and Aalborg Sygehus (Drs Frost and Johnsen), Aarhus,
Denmark; Centre for Research in Health & Social Statistics, Danish National
Research Foundation, Copenhagen (Ms Engholm and Mr Møller); and Department
of Vascular Surgery, Viborg Sygehus, Viborg, Denmark (Dr Henneberg).
Reprints: Lars Frost, MD, PhD, Department of Cardiology, Aarhus Amtssygehus,
DK-8000 Aarhus C, Denmark (e-mail: l.frost{at}dadlnet.dk).
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