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Oral Anticoagulation and Hemorrhagic Complications in an Elderly Population With Atrial Fibrillation
Mhairi Copland, BSc, MBChB, MRCP;
Isobel D. Walker, MD, FRCP, FRCPath;
R. Campbell Tait, BSc, FRCP, MRCPath
Arch Intern Med. 2001;161:2125-2128.
ABSTRACT
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Background Warfarin sodium therapy in patients with atrial fibrillation markedly
reduces the incidence of embolic stroke. However, in elderly patients warfarin
therapy is often underused owing to the perceived higher risk of hemorrhagic
complications.
Objectives To assess the quality of anticoagulant control and the incidence of
hemorrhagic complications and stroke in an elderly population (>75 years old)
compared with a younger control group (between 60 and 69 years) and to assess
the quality of anticoagulant control and incidence of hemorrhagic complications
in those patients who recently commenced receiving warfarin therapy (first
year of therapy).
Patients and Methods In this retrospective follow-up study, anticoagulant control and the
incidence of hemorrhagic complications and stroke were assessed in an elderly
population (>75 years old) compared with a younger control group (between
60 and 69 years), all with atrial fibrillation(target international normalized
ratio [INR] 2.5) and attending a hospital outpatient anticoagulant clinic.
Results A total of 328 patients were studied over a 21-month period. There were
204 patients in the control group providing 288 patient-years of follow-up
and 124 patients in the elderly group providing 170 patient-years of follow-up.
The percentage of INR results in the target range was not statistically significantly
different between the elderly and control groups (71.5% vs 66.1%) and the
occurrences of incidences of INR greater than 7 were 4.2% in the control group
and 4.7% in the elderly group (P = .96). The incidences of major
hemorrhage were 2.8% per year in the elderly group and 2.9% per year in the
control group (P = .96); overall incidence was 2.8% (95% confidence
interval, 1.3%-4.4%). One hundred one of the 328 patients studied commenced
warfarin therapy during or within 3 months of the start of the study. In this
induction group, 62.1% of INRs were within the target range compared with
70.9% of INRs in patients who had been receiving warfarin therapy for more
than 3 months at the start of the study (P = .002). The incidences
of INR greater than 7 and major hemorrhage were 7.9% per year and 6.9% per
year, respectively, in the cohort who recently began warfarin therapy compared
with 3.4% per year and 1.7% per year in the group who were receiving warfarin
therapy for more than 3 months.
Conclusion While it was impossible to consider any selection bias at the level
of referral to the clinic, these findings suggest that the elderly population
attending our anticoagulant clinic did not have poorer anticoagulant control
or an increased incidence of hemorrhage while receiving warfarin therapy.
INTRODUCTION
ATRIAL FIBRILLATION (AF) is an important independent risk factor for
ischemic stroke and is associated with a 6-fold increase in risk.1 A recent meta-analysis of 6 randomized trials studying
antithrombotic therapy for stroke prevention showed a relative risk reduction
of 62% for those receiving warfarin sodium therapy compared with placebo and
36% compared with aspirin.2-8
Warfarin provides optimum protection against ischemic stroke at an international
normalized ratio (INR) of 2.0 to 3.0.9 An INR
greater than 3.0 would be protective against ischemic stroke but increases
the risk of hemorrhagic complications. In patients who have AF, increasing
age is a known risk factor for ischemic stroke.10-11
These patients, therefore, benefit from anticoagulation therapy. However,
the elderly population is thought to have a greater risk of hemorrhagic complications,
and warfarin therapy tends to be underused.12
In this study, the quality of anticoagulant control and the incidence
of hemorrhagic complications and stroke were assessed in an elderly population
(>75 years old) compared with a younger control group (between 60 and 69 years).
In addition, we assessed the quality of anticoagulant control and the incidence
of hemorrhagic complications in those patients who recently commenced receiving
warfarin therapy (first year of therapy). All patients had AF with a target
INR of 2.5 and were attending the hospital outpatient anticoagulant clinic.
PATIENTS, MATERIALS, AND METHODS
In a retrospective follow-up study of all patients between 60 and 69
years of age and those older than 75 years who had AF and were attending the
hospital anticoagulant clinic were enrolled in this study. The only exclusion
criterion was those patients who had a prosthetic heart valve.
A total of 328 patients (143 males and 185 females) were studied over
a 21-month period (January 1, 1998, to September 30, 1999). Those patients
receiving warfarin therapy prior to January 1, 1998, and those commencing
warfarin therapy between January 1, and December 31, 1998, were included in
this study. Quality of anticoagulant control was assessed by calculating the
patient's percentage of attendances at the anticoagulant clinic where the
INR was within an acceptable target range of 1.8 to 3.3 (mean ± standard
acceptable in the United Kingdom, 2.5 ± 0.75). The incidence of hemorrhagic
complications was based on the number of bleeding events per patient-year
of follow-up while receiving warfarin therapy. A major hemorrhage was any
bleeding event that was fatal; involved the central nervous system; or required
hospitalization, blood transfusion, or surgical intervention. Statistical
analyses were performed using the  2 test. P<.05 was statistically significant.
RESULTS
The subject characteristics are detailed in Table 1. There were 204 patients in the control group (mean age,
64.7 years) providing 288 patient-years of follow-up and 124 in the elderly
group (mean age, 78.3 years; age range, 75-89 years) providing 170 patient-years
of follow-up. Incomplete data were available for 6 patients who were lost
to follow-up from the anticoagulant clinic.
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Table 1. Subject Characteristics of Elderly vs Control Group
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A total of 3010 INRs were checked in both groups during the 21-month
study period (average, 6.6 per patient-year). There were a total of 659 high
INRs (>3.3), 448 in the control group (1.6 per patient-year), and 211 in the
elderly group (1.2 per patient-year). There were a total of 259 low INRs (<1.8),
156 in the control group (0.6 per patient-year) and 103 in the elderly group
(0.6 per patient-year). Therefore, overall 68.2% of INRs were in the target
range; 66.1% in the control group and 71.5% in the elderly group (P = .13). There were 20 episodes of an INR greater than 7: 12 in the
control group and 8 in the elderly group (0.7% in both groups). The incidences
of major hemorrhage were 2.8% per year and 2.9% per year in the control and
elderly groups, respectively (P = .96); overall incidence
was 2.8% (95% confidence interval, 1.3%-4.4%). The overall incidence of intracranial
hemorrhage was 0.9%; 0.7% in the control group and 1.2% in the elderly group
(P = .61).
The details of patients with hemorrhagic complications are given in Table 2. All patients discontinued warfarin
therapy following a bleeding episode. One patient started receiving clopidogrel
therapy, and 1 patient commenced receiving aspirin therapy following colonic
polypectomy. Two patients died following intracranial hemorrhage—1 in
the elderly group and 1 in the control group. No patients died of gastrointestinal
tract hemorrhage; however, 1 patient with mitral valve disease died of congestive
heart failure following a gastrointestinal tract hemorrhage.
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Table 2. Characteristics of 13 Patients With Bleeding Episodes*
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In the course of the study, there were 3 episodes of ischemic stroke
in 2 patients in the elderly group. The patients were both women, aged 79
and 82 years with therapeutic INRs of 2.5 and 3.4, respectively, at the time
of stroke. Information regarding the INR at the time of the first ischemic
event in the patient having 2 strokes was unavailable. Both of these patients
died of ischemic stroke.
One hundred one of the 328 patients studied commenced receiving warfarin
therapy during or within 3 months of the start of the study (Table 3). In this induction group in the first year of warfarin
therapy, 62.1% of INRs were within the target range compared with 70.9% of
INRs in patients who had been receiving warfarin therapy for longer than 3
months at the start of the study (P<.005). The
incidence of INR greater than 7 was 7.9 episodes per 100 patient-years in
the cohort in the first 12 months of warfarin therapy compared with 3.4 episodes
per 100 patient-years in the group receiving warfarin therapy for longer than
3 months. The incidence of major hemorrhage was 6.9 episodes per 100 patient-years
in the cohort in the first 12 months of warfarin therapy compared with 1.7
episodes per 100 patient-years in the group receiving warfarin therapy for
longer than 3 months (P<.005). None of the patients
in the cohort who recently commenced receiving warfarin therapy bled within
the first 3 months of therapy; however, 7 of the 101 patients in this group
had major bleeding episodes between 5 and 12 months of therapy. There was
no statistically significant difference in the risk of serious hemorrhage
between the control and elderly groups (5.9 % vs 7.4%, respectively) in the
first year of warfarin therapy.
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Table 3. Characteristics of Elderly and Control Groups: Long vs Short
Duration of Therapy
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COMMENT
These findings suggest the elderly population attending our anticoagulant
clinic did not have poorer anticoagulant control or an increased overall incidence
of hemorrhage while receiving warfarin either in the first year of treatment
or when receiving long-term therapy. These results are in accord with those
of a recently published study that showed that in clinical practice the incidence
of hemorrhagic complications and stroke were comparable with those in randomized
studies despite statistically significant differences in patient characteristics
and poorer anticoagulant control.13 It was
impossible to consider any selection bias at the level of referral to the
clinic. Potentially, referring cardiologists may have selected antiplatelet
therapy for elderly patients with a complicated medical history or perceived
high risk of bleeding.
Although previous studies have suggested an increased risk of intracranial
hemorrhage in elderly patients,12 our results
do not support this. Two of the 124 patients in the elderly group had intracranial
bleeding compared with 2 of the 204 patients in the control group (P = .61). While the numbers are small, the outcome for patients with
intracranial hemorrhage was poor with a mortality of 50% (2 of 4 patients).
These results confirm those of previous studies that recent commencement
of warfarin therapy (<1 year in this study) is a strong independent risk
factor for major hemorrhage.14 The risk was
not greater in the elderly group compared with the control group. Indeed,
the elderly group had superior anticoagulant control during the first year
of therapy and a lower incidence of hemorrhagic complications, although the
difference was not significant.
CONCLUSIONS
These results demonstrate that long-term anticoagulation with warfarin
therapy should be considered in all patients with AF who do not have contraindications.
Although there is no comparison with controls who did not receive warfarin
therapy, this study provides evidence to support the cautious use of warfarin
for stroke prevention in the elderly population with AF as the observed rate
of ischemic stroke is low and there is no increased risk of hemorrhagic adverse
effects.
AUTHOR INFORMATION
Accepted for publication February 12, 2001.
Presented as a poster at the British Society for Haematology annual
meeting, Bournemouth, England, March 28, 2000, and as a prize-winning oral
presentation at the West of Scotland Blood Club annual scientific meeting,
Glasgow, Scotland, May 24, 2000.
Corresponding author: Mhairi Copland, BSc, MBChB, MRCP, Department
of Haematology, Macewan Bldg, Glasgow Royal Infirmary, 84 Castle St, Glasgow
G4 0SF, Scotland.
From the Department of Haematology, North Glasgow University Hospitals
National Health Service Trust, Glasgow, Scotland.
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