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(Stroke. 2000;31:1217.)
© 2000 American Heart Association, Inc.

Original Contributions

Warfarin for Stroke Prevention Still Underused in Atrial Fibrillation

Patterns of Omission

Natan Cohen, MD; Dorit Almoznino-Sarafian, MD; Irena Alon, MD; Oleg Gorelik, MD; Margarita Koopfer, MD; Shulamit Chachashvily, MD; Miriam Shteinshnaider, MD; Vladimir Litvinjuk, MD David Modai, MD

From the Department of Internal Medicine F, Assaf Harofeh Medical Center, Affiliated to Sackler Faculty of Medicine, Tel Aviv University, Zerifin, Israel.

Correspondence and reprint requests to Natan Cohen, MD, Department of Internal Medicine F, Assaf Harofeh Medical Center, Zerifin 70300, Israel.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose—The value of warfarin in preventing stroke in patients with chronic atrial fibrillation is well established. However, the prevalence of such treatment generally lags behind actual requirements. The aim of this study was to evaluate doctor- and/or patient-related demographic, clinical, and echocardiographic factors that influence decision for warfarin treatment.

Methods—Between 1990 and 1998, 1027 patients were discharged with chronic or persistent atrial fibrillation. This population was composed of (1) patients with cardiac prosthetic valves (n=48), (2) those with increased bleeding risks (n=152), (3) physically or mentally handicapped patients (n=317), and (4) the remaining 510 patients, the main study group who were subjected to thorough statistical analysis for determining factors influencing warfarin use.

Results—The respective rates of warfarin use on discharge in the 4 groups were 93.7%, 30.9%, 17.03%, and 59.4% (P=0.001); of the latter, an additional 28.7% were discharged on aspirin. In the main study group, warfarin treatment rates increased with each consecutive triennial period (29.7%, 53.6%, and 77.1%, respectively; P=0.001). Age >80 years, poor command of Hebrew, and being hospitalized in a given medical department emerged as independent variables negatively influencing warfarin use: P=0.0001, OR 0.30 (95% CI 0.17 to 0.55); P=0.02, OR 0.59 (95% CI 0.36 to 0.94); and P=0.0002, OR 0.26 (95% CI 0.12 to 0.52), respectively. In contrast, past history of stroke and availability of echocardiographic information, regardless of the findings, each increased warfarin use (P=0.03, OR 1.95 [95% CI 1.04 to 3.68], and P=0.0001, OR 3.52 [95% CI 2.16 to 5.72], respectively).

Conclusions—Old age, language difficulties, insufficient doctor alertness to warfarin benefit, and patient disability produced reluctance to treat. Warfarin use still lags behind requirements.

Key Words: anticoagulation • aspirin • atrial fibrillation • stroke • thromboembolism • warfarin

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The value of warfarin therapy in the prevention of cardioembolic events in patients with nonrheumatic atrial fibrillation has been increasingly demonstrated in the last decade.^{1 2 3 4 5 6 7 8 9} In a number of recent publications, it has been substantiated that such therapy is capable of preventing more than two thirds of these events, with low rates of hemorrhagic complications.^{1 8 9 10} On the other hand, recent retrospective analyses have demonstrated that the prevalence of warfarin use lags considerably behind actual requirements.^{11 12 13 14 15 16 17 18 19 20 21 22 23} The responsibility for this gap is shared by both physician and patient factors. The pivotal physician-related factor is an insufficiently balanced evaluation of the risk versus benefit. This has to be tailored for each patient individually, taking into consideration features that variably modify the risk for embolism, such as previous stroke, hypertension, old age, congestive heart failure, coronary heart disease, or diabetes mellitus,^{1 10 16 20 24} against the risk of bleeding. An additional factor is the physician’s assessment of chances to obtain adequate long-term patient cooperation. Patient-related factors may include individual preferences regarding relevant options of treatment (ie, warfarin versus aspirin or no treatment) and various cultural, intellectual, and technical inconveniences associated with frequent visits to the clinic.

The majority of reports on this issue originate in the United States and United Kingdom. Because institution and maintenance of chronic warfarin therapy is dependent on a multitude of factors, some of them universal and some peculiar to each population, this study was undertaken to investigate in detail the role played by these factors in the implementation of warfarin treatment in the setting of a regional university hospital in Israel serving a population of heterogeneous composition. We focused on a selected group of patients who did not have prosthetic valves and were free of bleeding risks or any disability that might deter the physician from warfarin use.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background
Assaf Harofeh Medical Center is a 600-bed regional university hospital serving almost exclusively a population that increased from 320 000 in 1989 to 380 000 in 1997, mainly through absorption of new immigrants from the previous Soviet Union and Ethiopia. The number of patients hospitalized annually during this period increased from 39 500 to 57 800. The hospital comprises 6 medical departments, all admitting similar patient populations. Patients are mostly referred by their family physicians, who are general practitioners or specialists in family medicine. The composition of patient population in the region varies considerably with respect to country of origin, duration of residence in Israel, knowledge of the Hebrew language, cultural background, and socioeconomic status. The latter is reflected by location of residence, with urban area A being inhabited by the more prosperous population segment. The distance from any point in the region to the hospital does not exceed 10 miles. Within the region there are a number of nursing homes that refer their patients to the hospital in case of need.

Patients
To assess the use of anticoagulation therapy, the charts of all patients admitted to the departments of medicine during the period 1990 through 1998 with atrial fibrillation as one of the diagnoses were reviewed. For this purpose we used the International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM), diagnostic code of 427.31.

Composition of Patient Subsets and Main Group
Included in the study were patients in whom chronic or persistent atrial fibrillation was recorded. The charts of the following 4 patient subsets were set aside for separate statistical analysis. First, those with prosthetic valves, who served as a yardstick for maximal prevalence of warfarin use. Second, patients with contraindications for warfarin due to increased bleeding risks, ie, those with a history in the previous 6 months of gastrointestinal, intracranial, or retinal hemorrhage, or any other significant internal bleeding. We also excluded patients with peptic ulcer, renal failure (serum creatinine >2.5 mg), anemia (hemoglobin <10.5 g/dL), hemorrhagic tendency or blood dyscrasia, liver cirrhosis or impaired hepatic function (aspartate and/or alanine aminotransferase >3 times of the upper limit of normal), significant surgery performed within the previous month, malignant disease, large pericardial effusion, aortic aneurysm; and those with recurrent syncope, falls, or seizures. Third, patients with limited cooperation abilities, ie, those who suffered from psychiatric disorders or dementia of all causes and/or patients who were bedridden. The remaining patients, free of any conditions that would a priori encourage or discourage the physician to use warfarin, constituted the main study group.

Data Processing
All patient records were reviewed by physicians who were members of this department of medicine. The data examined included demographic data, disorders commonly coexisting with atrial fibrillation, valvular abnormalities as demonstrated by echocardiography (where available), potential risk factors for embolic events, sequential triennial periods, interdepartmental variability, and warfarin treatment according to the specific subset of patients.

Statistical Analysis
Data were analyzed with respect to patients. For those with >1 hospitalization, only the most recent one was considered. In the first stage a univariate analysis was applied to evaluate the effect of the various variables on the decision for warfarin treatment. The ² test was used, and significance level was set at P0.05. In the second stage a logistic regression analysis was performed. All variables for which P<0.2 in the univariate analysis were introduced into a logistic model. It was thus possible to identify the variables that independently and significantly influenced the decision to administer warfarin.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Patient Classification
Following elimination of 37 patient files with unsatisfactory documentation, 1293 patients remained on admission. Table 1 depicts the classification of this patient population into the 4 subsets defined.

View this table: [in this window] [in a new window]   Table 1. Classification of Patients With Chronic or Persistent Atrial Fibrillation Admitted and Discharged During the Years 1990–1998

Data on Admission Versus Discharge for the Entire Study Population
Of the 1219 patients (Table 1) who comprised the last 3 groups (patients with prosthetic valves excluded) on admission, 45% were men and 55% women. Mean±SD age was 73.2±11.1 years; 27.8% were aged <70 years, 37.6% were between 70 and 80 years, and 34.6% were >80 years. Of this patient population, 28.1% were on warfarin or warfarin and aspirin, and 20% were on aspirin. Of the 1219 patients admitted, 240 died during the last hospital stay. Of the 979 remaining patients, 41% were discharged on warfarin or warfarin and aspirin, and 31.4% were discharged on aspirin.

Rates Of Warfarin Use According to 4 Subsets on Discharge
Of the 4 patient subsets (Table 1), the respective numbers and percentages of patients discharged on warfarin were 45 (93.7%), 47 (30.92%), 54 (17.03%), and 303 (59.4%); P=0.001.

Rates of Warfarin Use in the Main Study Group
Table 2 illustrates various data pertaining to the main study group consisting of 575 patients on admission and 510 on discharge, with 65 in-hospital fatalities. On admission 45.2% were men and 54.8% women, with a mean±SD age of 70.1±10.7 years. In this population also the rates of recommendation for warfarin and/or aspirin on discharge were substantially higher than those on admission (59.4% and 28.7% versus 38% and 17%, respectively). Of the 65 fatalities, 15 were due to stroke, 6 to sudden death, and the remaining 44 to various causes.

View this table: [in this window] [in a new window]   Table 2. Admission Characteristics of the 575 Patients Constituting the Main Study Group

Table 3 illustrates demographic, clinical, and echocardiographic data of the main study group versus the physicians’ decision to use warfarin. Of 510 patients discharged, 72% suffered from 1 or more conditions defined in the ACCP guidelines as high risk for cardioembolic stroke.¹ On univariate statistical analysis, gender and socioeconomic status did not affect the decision for anticoagulation. However, old age, poor command of Hebrew, short duration of residence in Israel, atrial diameter of <4.5 cm, coronary heart disease, and being hospitalized in a given medical department were associated with diminished rates of warfarin use (P=0.001, P=0.005, P=0.002, P=0.001, P=0.056, and P=0.001, respectively). Mitral stenosis, the availability of echocardiographic data regardless of the findings, and hypercholesterolemia emerged as factors that positively influenced the doctors’ decision to treat (P=0.001, P=0.001, and P=0.013, respectively). Being single and having a past history of stroke approached significance (P=0.065 and P=0.078). Table 4 depicts the results of the logistic regression analysis applied to all the significant parameters in Table 3. Patients aged >80 and those between 70 and 80 years were treated less frequently compared with those <70 years (P=0.0001, OR 0.30 [95% CI 0.170 to 0.551], and P=0.08, OR 0.64 [95% CI 0.396 to 1.063], respectively). In addition, poor knowledge of Hebrew and being hospitalized in a given medical department were additional independent variables that influenced the decision to deny warfarin (P=0.02, OR 0.59 [95% CI 0.369 to 0.948], and P=0.0002, OR 0.26 [95% CI 0.129 to 0.526], respectively). By contrast, availability of echocardiographic data, irrespective of atrial diameter, as well as a previous history of stroke were each independently associated with a greater tendency for warfarin use (P=0.0001, OR 3.52 [95% CI 2.167 to 5.723], and P=0.03, OR 1.95 [95% CI, 1.041 to 3.681], respectively).

View this table: [in this window] [in a new window]   Table 3. Characteristics of the 510 Discharged Patients of the Main Study Group, With Rates of Warfarin Use on Discharge

View this table: [in this window] [in a new window]   Table 3A. continued

View this table: [in this window] [in a new window]   Table 4. Independent Variables Influencing Warfarin Use: Results of Multivariate Logistic Regression Analysis

Rates of Warfarin Use in Sequential Triennial Periods in the Main Study Group
The percentage of patients discharged on warfarin increased significantly and progressively with time: 29.7% in 1990–1992, 53.6% in 1993–1995, and 77.1% during 1996–1998 (P=0.001).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In recent years compelling evidence has accumulated which indicates that appropriate warfarin treatment prevents cardioembolic events in approximately two thirds of patients with atrial fibrillation.^{1 8 9 10} However, in most publications, the percentage of patients so treated was substantially lower and varied in different reports.^{11 12 13 14 15 16 17 18 19 20 21 22 23} This means that a considerable number of patients subsequently suffered preventable strokes.

The primary patient population in this study, composed of 1219 patients (individuals with prosthetic valves not included), was similar in its age and gender distribution to populations in other reports.^{16 21 25} Rates of warfarin use on discharge were considerably greater than those on admission. This may reflect a greater tendency of specialists in internal medicine compared with family physicians to recommend anticoagulation. However, it still represents underuse of warfarin compared with the 60% who can safely and beneficially undergo anticoagulation therapy.²⁶

When the entire population was examined, the vast majority of patients with prosthetic valves (93.7%) were discharged on warfarin, as expected. An interesting finding was that in the patients with increased bleeding risks, 30.9% were discharged on warfarin. This would suggest that in selected cases consideration of all clinical circumstances of the individual patient favored warfarin treatment despite the risk of bleeding involved. Such an optimistic attitude was not evident in the group of patients with dementia, psychiatric disorders, and/or physical disabilities. Only 17% of these patients were discharged on warfarin. Theoretically, denial of treatment to these patients as a group is unjustified.¹³ The feasibility of adequate maintenance of warfarin therapy in such patients is dependent on a variety of factors, including physical and mental state, social conditions, and access to medical surveillance. These have to be weighed against any potential gain from warfarin treatment in preventing stroke, which in turn may result in further deterioration of physical and mental status. Thus, the decision to treat has to be tailored for each patient individually. Given the size of this patient population worldwide, it is surprising that this issue received little attention in the literature.¹³

On discharge, the main study group was composed of 510 patients not carrying prosthetic valves and free of contraindications for anticoagulation. As expected, a considerably greater percentage of these patients (59.4%) received warfarin. However, this finding still falls short of the actual requirements, because the vast majority of these patients should have been expected to receive warfarin.

Old age emerged as the most important independent factor that negatively affected doctors’ decision for anticoagulation. Thus, while 73.1% of patients aged <70 years were discharged on warfarin, 57.7% of those between 70 and 80 years and only 37.2% >80 years, respectively, were prescribed warfarin. The inverse correlation between age and warfarin use has been previously reported.^{9 13 16 17 18} This is in complete disagreement with information in the literature which indicates that the risks for embolic events as well as chances of prevention rise with age.^{1 10 17} On the other hand, the alleged increased bleeding risks in the very old age group is still controversial.^{27 28} Thus, odds are in favor of warfarin therapy in this age group.

Although no correlation emerged between gender or socioeconomic status and warfarin treatment, knowledge of the language, a factor not previously evaluated, was found to independently and negatively influence decision to treat. It seems that this mainly represents the quality of doctor-patient communication, which determines patient understanding concerning the advantages and risks involved in warfarin treatment. This correlation may be applicable to many countries with a sizeable population of new immigrants.

The finding that demonstrates a significantly decreased use of warfarin in a given department recalls another report¹⁵ in which considerable differences in warfarin use were found among 5 hospitals in Pennsylvania. It probably reflects variability in the awareness and alertness to the ongoing relevant information in the literature.

In the recent ACCP consensus conference on antithrombotic therapy¹ and additional publications,^{10 16 20 24} prior stroke, hypertension, diabetes mellitus, older age, and impaired left ventricular function were cited as high-risk factors for cardioembolic events in patients with nonrheumatic atrial fibrillation. In the present study, only a history of previous stroke was associated with a greater prevalence of warfarin treatment.

Data in the literature are inconsistent concerning the impact of an enlarged left atrium on the risk of stroke.^{1 29 30} Univariate analysis of this parameter in the main study group in this investigation (Table 3) suggests that atrial diameter >4.5cm was associated with an increased prevalence of warfarin use (P<0.001). However, on multiple regression analysis (Table 4), the availability of echocardiographic information per se, rather than atrial diameter, emerged as an independent variable that significantly enhanced inclination to treat. It is conceivable that the availability of such data sharpened doctors’ alertness to warfarin treatment in the presence of diverting factors such as comorbid conditions.^{20 28}

The demonstration of a substantial progressive rise in the percentage of patients who received warfarin from 1990 to 1998 most probably reflects the growing conviction of the effectiveness of this treatment. In this respect, it is interesting to note that in recent reports warfarin use increased during 1990 through 1996³¹ and plateaued in the period 1993–1996.¹¹ The present survey is, to our knowledge, the only one reporting data extending through 1998 and demonstrating that warfarin use continued to rise during 1996–1998 to 77.1%.

In conclusion, internists’ use of warfarin for atrial fibrillation in this study still lagged considerably behind proved benefit-versus-risk data. This is true even for patients free of absolute or relative contraindications. Thus, ongoing encouragement of the medical community to intensify anticoagulation treatment in patients with atrial fibrillation is required.

	Acknowledgments

 
The authors would like to thank Ms Ravit Bidlovski for her cooperation in preparation of the manuscript.

Received January 20, 2000; revision received March 13, 2000; accepted March 13, 2000.

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