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the Departments of Neurology (J.S., P.A.B., N.E.A., P.B., Y.B., L.R.) and Medicine (D.S.), Auckland City Hospital, and Geriatric Medicine, Auckland City Hospital (A.C.) and Middlemore Hospital (A.K.), Auckland, New Zealand.
Abstract
Background and Purpose— Ischemic stroke patients in atrial fibrillation (AF) have a 10% to 20% risk of recurrent stroke. Warfarin reduces this risk by two thirds. However, warfarin is underutilized in this patient group. We performed a prospective study to determine the reasons why warfarin is not started in these patients.
Methods— All patients with AF-associated ischemic stroke over a 12-month period were identified. Demographic and other data, including whether warfarin was commenced or recommended at discharge, and if not why not, were recorded.
Results— Ninety-three of 412 (23%) ischemic stroke patients had paroxysmal or permanent AF. Of these patients, 17 (18%) died, 48 (52%) were discharged home, and 28 (30%) were discharged to institutional care. Only 13 of 64 (20%) patients with known AF were taking warfarin at stroke onset. Warfarin was started (or recommended) in 35 of 76 (46%) survivors. Of those not commenced on warfarin, 32 (78%) were dependent (P<0.001) and 23 (56%) were discharged to institutional care (P<0.001). Warfarin was not started because of severe disability and frailty in 13 (32%), risk of falls in 12 (30%), and limited life expectancy in 4 (10%).
Conclusions— In this cohort of patients with AF, warfarin was primarily underutilized before stroke onset, and it was too late to use anticoagulation, in approximately half, once a stroke had occurred. The decision to start or continue anticoagulation requires clinical judgment and should be made on a case by case basis after a complete risk benefit assessment.
Key Words: anticoagulants atrial fibrillation stroke, ischemic warfarin
Introduction
People in nonvalvular atrial fibrillation (AF) who have had an ischemic stroke have a 10% to 20% risk of another stroke within the next 1 to 2 years.1 In clinical trials, warfarin reduces the risk of a further ischemic stroke of any type by 62% to 70%,2 and the risk of cardioembolic infarction is reduced by 83%.3,4 Warfarin also reduces mortality and is cost-effective in this group of patients.5 Despite clear benefits, anticoagulant therapy continues to be underutilized. Only half of AF-associated ischemic stroke patients are commenced on anticoagulant therapy.6,7
There are many reasons why anticoagulant therapy is not started, including physician and patient concerns about the risk of falls and hemorrhagic complications and barriers related to healthcare systems.8 Previous studies examining why patients are not anticoagulated have mainly been retrospective chart reviews. We performed a prospective analysis of all people admitted to our institution with AF-associated ischemic stroke over 12 months to determine the reasons for not commencing warfarin after the stroke. The aim was to determine the reasons for the discrepancy between clinical trial evidence and everyday practice.
Methods
All patients >15 years of age with an ischemic stroke and known or newly diagnosed permanent or paroxysmal AF were prospectively identified over a 12-month period from March 2004. Those presenting with intracerebral hemorrhage or transient ischemic attacks (TIAs) were excluded. Stroke was defined using the World Health Organization definition.9 All patients had been admitted to our institution, which is the district general hospital for a population of 400 000 and the tertiary neurology center for a regional population of 1.2 million. There is a 6-bed acute stroke unit and a stroke team consisting of specialist stroke physicians, nurses, and allied health staff, who see all stroke patients.
Patients were seen in the acute stroke unit or in other hospital wards. Data were recorded on a form modified from the stroke service database that is completed for all stroke patients. The CHADS2 score, designed to quantify stroke risk in patients with AF, was calculated for those patients known to be in AF before stroke.10 The CHADS2 score is formed by assigning 1 point each for congestive heart failure, hypertension, age 75 years or older, diabetes and 2 points for a past history of stroke or TIA. A modified Rankin Scale (mRS) score was recorded at the time of discharge. Poor outcome was defined as mRS 3.
There are 2 preparations of warfarin sodium available in New Zealand: Marevan (GlaxoSmithKline) and Coumadin (Healthcare Logistics). Patients take warfarin on a daily basis, and family practitioners monitor the international normalized ratio (INR). The reasons for not commencing warfarin in hospital were determined from the clinical notes, where this was documented, and by contacting the attending medical team when this was not clear. The main reason for not starting warfarin was defined as the "primary reason." Other factors that contributed to a decision not to use warfarin were classified as "secondary reasons."
Results
A total of 412 patients were admitted with an ischemic stroke over the 12-month study period. Ninety-three (23%) had AF-associated stroke (50 women; mean age 80; range 46 to 96 years) and are the subjects of this study. Sixty four (69%) were known to be in AF, and 29 (31%) were diagnosed as having AF during the admission. The AF was permanent in 64 (69%) and paroxysmal in 29 (31%) patients. Five patients (5%) were treated with tissue plasminogen activator.
Comorbidities associated with an increased stroke risk included hypertension in 58 (62%), congestive heart failure in 23 (25%), and diabetes mellitus in 16 (17%). Thirty-four patients (37%) had had a previous stroke or TIA, of whom 8 (24%) were taking warfarin, 20 (59%) were taking antiplatelet therapy alone, and 6 (18%) were taking no antithrombotic therapy.
Thirteen of 64 (20%) patients known to have AF were taking warfarin at the time of hospital admission. In these 13 patients, the mean INR was 1.8 (SD 0.89; range 0.9 to 3.5), and only 2 (15%) had an INR of between 2.0 and 3.0. The median CHADS2 score in the 64 known AF patients was 2.5 (interquartile range 1.5 to 4). Forty-eight had a CHADS2 score of 2, only 8 of whom were taking warfarin. A CHADS2 score of 2 corresponds to a stroke rate without antithrombotic therapy of 4.0 per 100 patient years.10 In general, the 51 patients with known AF not taking warfarin at admission had a poor outcome, with 25 (49%) dependent on others for care at discharge and 14 (27%) requiring institutional care.
Seventeen (18%) patients died in hospital. Three patients died while taking warfarin; 2 had a low INR (0.9 and 1.2), and a third died from a recurrent ischemic stroke despite an INR of 3.4. In no cases did hemorrhagic complications of anticoagulant therapy contribute to death. Of the 76 survivors, 43 (57%) were dependent (mRS 3), and 33 (43%) were independent (mRS 2) at the time of discharge (Table 1). Forty-eight (63%) patients were able to return home, of whom 31 (65%) were independent and 17 were dependent. Twenty-eight (37%) required ongoing institutional care, with 26 dependent on others for activities of daily living (2 23.7502; P<0.001).
Warfarin was recommended in 35 (46%) of the 76 survivors (Table 1); 28 were taking warfarin at discharge, and in 7 there were recommendations for the patients’ general practitioner to commence warfarin at a specified time after discharge. When these 7 patients were followed up some months later, only 4 had actually started warfarin. A decision not to prescribe warfarin had been made in 41 (54%) of the 76 survivors at the time of discharge, and antiplatelet therapy was started in 37 of these patients. Four patients with an mRS score of 5 and limited life expectancy were not prescribed any antithrombotic therapy.
Patients not commenced on warfarin were more likely to be dependent and discharged to institutional care (Table 1). In contrast, patients commenced on warfarin were more likely to be independent and discharged home. Nine patients who were independent at discharge were not commenced on warfarin because of risk of falls (4 patients), medication interactions or intolerance (2), risk of gastrointestinal hemorrhage (1), coincidental brain tumor (1), and physician choice (1).
Most patients had >1 reason for not commencing warfarin as secondary stroke prevention (Table 2). The most common primary reasons were severe disability and frailty (32%), high risk of falls (30%), and limited life expectancy (10%). Warfarin was not started in 1 patient because of a previous adverse event on warfarin and in another because of potential drug interactions. In 2 patients with no clear contraindication to warfarin, the attending physicians had either not considered or had chosen not to give anticoagulant therapy. In no patient was age or concerns about compliance given as the primary reason for not commencing warfarin.
Survivors were not systematically followed after discharge from hospital. However, we identified 3 of 41 patients in whom a decision not to anticoagulate was subsequently reversed. In 1 of these patients, medications with potential interactions with warfarin had been stopped, and 2 had a significant functional improvement. It is important to keep the decision not to start warfarin under review.
Discussion
To our knowledge, this is the first prospective observational study to investigate why people with AF-associated ischemic stroke are not started on anticoagulant therapy. Only approximately half of survivors were commenced on anticoagulant therapy before discharge from hospital. The most frequent reasons for not starting warfarin were severe disability and limited life expectancy, usually as a consequence of the incident stroke. High risk of falls was also a common reason for not starting warfarin with most of these patients unable to mobilize independently.
That only half of the survivors in this study could be started on warfarin reflects the poor prognosis from AF-associated ischemic stroke. The in-hospital mortality in this study was high (18%) compared with an 8% mortality from all ischemic strokes in our institution.11 More than half of the survivors were dependent in their activities of daily living and were discharged to hospital level institutional care. In the Framingham Study, AF-associated stroke was nearly twice as likely to be fatal, and functional deficits among survivors were more likely to be severe compared with non-AF stroke.12
This study suggests that the findings from clinical trials may not always be generalized to everyday practice. Trial participants are usually carefully selected and monitored. Only 8% of the 17 046 patients screened were enrolled into the Stroke Prevention in Atrial Fibrillation primary prevention study.13 Patients with repeated falls or unstable gait, hemorrhage in the preceding 6 months, chronic alcohol habituation, and age >75 years of age (for the first part of the study) were excluded. In the European Atrial Fibrillation trial of secondary prevention after TIA or minor stroke, 35% of patients were ineligible for anticoagulant therapy, with the exclusion of those with moderate to severe disability (mRS >3).14 Veterans Affairs co-operative study-Stroke Prevention In Nonrheumatic Atrial Fibrillation (VA-SPINAF) looked at both primary and secondary stroke prevention and excluded 93% of those screened; 43% of these were on the basis of a contraindication to anticoagulation.15
Anticoagulant therapy was both underutilized and inadequately monitored in those with known AF before stroke admission. This is despite three fourths of the patients having increased stroke risk with CHADS2 scores of 2. The SAFE II study found that only 22% of patients with new ischemic stroke and nonvalvular AF were taking oral anticoagulant therapy at admission to hospital.16 In another study, only 27% of patients with known AF, who had 1 stroke risk factor and no contraindications to warfarin, were taking warfarin at the time of stroke and only 27% of this group had an INR of 2.0 to 3.0.6 Failure to appropriately anticoagulate AF patients as primary stroke prevention represents a missed opportunity to prevent the significant mortality and morbidity that is caused by AF-associated ischemic stroke.
Reasons for underutilization of warfarin include age, compliance issues, bleeding risk, patient disability, alcohol use, and physician fear of hemorrhage.8,16–20 In this study, potentially poor compliance was only raised as a secondary reason for not commencing anticoagulation in 1 patient. The risk of recurrent spontaneous upper gastrointestinal tract hemorrhage is not increased once gastrointestinal bleeding has been treated.21,22 Proton pump inhibitors reduce the risk of recurrent nonsteroidal anti-inflammatory drug-induced gastrointestinal tract hemorrhage.23 Warfarin is often withheld on the basis of advanced age, yet older people with AF often have the most to gain from such therapy.24 Patients at high risk for falls with AF are at substantially increased risk of intracranial hemorrhage. However, if they have multiple stroke risk factors, they may still benefit from anticoagulant therapy.25,26
Our study has a number of limitations. We acknowledge that the decision not to commence warfarin was based on clinical judgment and that practice may vary in different locations and between individual physicians. This is particularly relevant when risk of falls is considered. Patients with stroke are often at a much greater risk of falling than AF patients recruited into primary prevention trials. However, our findings reflect everyday practice because we included all patients with stroke admitted to our hospital over 12 months. Patients were not excluded on the basis of age, type of AF, or stroke severity. Contraindications to warfarin were determined at the time of hospital discharge, as opposed to admission, so that stroke-associated morbidity could be taken into account when a decision was made to anticoagulate or not. Patient preferences were also determined, which are more difficult to identify with retrospective chart reviews or administrative surveys.
In this cohort of all AF-associated ischemic stroke patients presenting to our institution, the underutilization of anticoagulation primarily occurred before stroke onset. Once a stroke had occurred, it was too late to use anticoagulant therapy in approximately half of the patients. The decision to start or continue anticoagulant therapy in patients with AF-associated stroke requires clinical judgment and should be made on a case-by-case basis following a complete risk benefit assessment.
Acknowledgments
Salary support for P.B. is provided by the Julius Brendel Trust.
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