NEUROLOGICAL PROGRESS

Stroke Prevention in Nonvalvuh Atrial Fibrillation: A Review of Prospective Randomized Trials Gregory W. Albers, MD," David G. Sherman, MD,? Daryl R. Gress, MD,$ J. E. Paulseth, MD, FRCP,$ and Palle Petersen, MD, PhDn

Patients with atrial fibrillation are at risk for cerebral embolism; however, the roles of chronic anticoagulation or antiplatelet therapy for stroke prevention in patients with nonvalvular atrial fibrillation have been controversial. Recently, the results of three large prospective randomized trials that examined the risks and benefits of warfarin or aspirin for stroke prophylaxis in patients with nonvalular atrial fibrillation were reported. All three studies revealed a reduction in the stroke rate for patients treated with warfarin and a small incidence of major bleeding. One of the studies also reported a reduced stroke rate in aspirin-treated patients. The reduction of thromboembolic events associated with chronic warfarin therapy appears to outweigh the risks of significant bleeding for most patients with nonvalvular atrial fibrillation. Aspirin may offer an alternative for subgroups of patients who are at low risk for stroke or those who are not good candidates for anticoagulation. Albers GW, Sherman DG, Gress DR, Paulseth JE, Petersen P. Stroke prevention in nonvdvular atrid fibrillation: a review of prospective randomized trials. Ann Neurol 1991;30:5 11-5 18

Patients with atrial fibrillation (AF) are at risk for cardiac embolization, and approximately 70% of clinically apparent cardiogenic emboli involve the brain, producing stroke or transient ischemic symptoms 111. The overall risk of stroke in patients with chronic AF is about 5% per year 11-31. One retrospective study suggested that anticoagulation can reduce embolic complications in patients with AF from 5% per year to less than 1% per year [4}. Despite these findings, routine anticoagulation of patients with AF has not generally been recommended 13, 5-7), primarily because of the concern about bleeding complications. In addition, antiplatelet therapy has not generally been recommended for these patients because it has been considered insufficient to prevent embolization from intracardiac thrombi {8}. AF is a heterogeneous disorder caused by a variety of factors and associated with a number of different medical conditions. It is associated with valvular and

nonvalvular causes. Valvular AF currently accounts for only about 20% of all AF and is primarily due to rheumatic heart disease [3}. The majority of AF is not associated with valvular disease but is commonly associated with other cardiovascular disorders such as hypertension and coronary artery disease. Chronic anticoagulation is standard therapy for patients with AF who have rheumatic mitral stenosis or prosthetic valves [3,9]. However, the role of anticoagulation for patients with nonvalvular AF (NVAF) has been uncertain because of inadequate data. The first prospective randomized studies to evaluate the role of chronic anticoagulant or antiplatelet therapy in patients with NVAF were recently completed. The studies are: the Copenhagen Atrial Fibrillation, Aspirin, Anticoagulation study (AFASAK) {lo]; the Stroke Prevention in Atrial Fibrillation study (SPAF) 111, 12); and the Boston Area Anticoagulation Trial for Atrial Fibrillation (BAATAF) 1131. The purpose of this review is

From the "Department of Neurology and Neurological Sciences, Stanford Universitv Medical Center. Stanford. and the Palo Alto VA Medical Center, ~ i i Alto, o CA; ?Division of Neurology, University of Texas Health Science Center at Antonio, Antofflo, m; $Department of Neurology, Massachusetts General Hospital, Boston, MA (on behalf of the Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators); $Department of Neurology, Hamilton Civic Hospitals, Hamilton, Ontario, Canada; and bepartment of Neurology, University Hospital, Rigshospitalet, Copenhagen, Denmark (on behalf of the Atrial Fibrillacion, Aspirin, Anticoagulation Study Investigators).

Received Jan 28, 1991, and in revised form Apr 4 . Accepted for publication Am - 5.. 1991. iddress correspondence ro Dr Abers, apamnent of and ~ ~ ~sciences, ~ Stanford l ~ universiry g i Medical ~ center, ~ CA 94305,

Copyright 0 1991 by the American Neurological Association

511

to evaluate the preliminary data from these studies in the context of existing information about anticoagulation and AF.

Table 1. Target Rangefor Intensity of Antimagalation and Aspirin Dose in the Prospective Trials

Risk Factors for Stroke i n Nonvalvular Atrial Fibrillation The population of patients with NVAF is diverse. Therefore, the prospective studies on NVAF attempted to include most types of patients; however, a few subgroups were excluded. These consisted primarily of patients who were suspected to be at either particularly high.or particularly low risk for stroke. The high-risk subgroups include patients with NVAF who had suffered a recent embolic event or acute myocardial infarction, or who had significant congestive heart failure or cardiomyopathy. Anticoagulation is generally recommended for these situations 131. The most well-established subgroup at low risk for stroke includes patients with lone AF, which is typically defined as AF unaccompanied by clinical evidence of coexisting cardiovascular disease. Lone AF accounts for about 10% of all AF. Estimation of the yearly stroke risk has varied, depending on the specific criteria used to define lone AF C14-161. Young patients with lone AF (those younger than 60 years) appear to have a stroke risk of less than 0.5% per year C7, 151. Because of this, one of the prospective studies (SPAF) excluded such patients from randomization to warfarin therapy and instead randomized these patients to receive aspirin or placebo. Paroxysmal o r intermittent AF may represent another low-risk group. Some recent studies suggested that paroxysmal fibrillation is associated with a lower risk for stroke than is chronic fibrillation C16, 171, although other studies showed no significant difference 141. Patients with both chronic sustained or intermittent AF were eligible in all studies except for the AFASAK trial. Another important determinant of stroke risk in AF is age [18, 191. The relative risk for stroke attributable to AF increases with age, and the majority of AF-associated stroke occurs in elderly patients. Therefore, in general, no upper age limit was adopted in the prospective trials and the average age of participants was about 7 0 years.

AFASAK SPAF BAATAF

Optimal Therapeutic Range for Oral Anticoagulation Recommendations for the intensity of oral anticoagulation therapy have changed significantly over the last decade. It has become increasingly clear that the American Heart Association's 1954 recommendation of a therapeutic prothrombin time (PT) ratio between 2.0 and 2.5 times control values is excessive when using commercial thromboplastins that are currently available in the United States {20). Thromboplastins vary

512 Annals of Neurology Vol 30 No 4

October 1991

INRa

PT Ratio"

Aspirin

2.8-4.2

1.5-2.0 1.3- 1.8 1.2-1.5

75 mgtday 325 mgiday

2.0-3.5 1.5-2.7

~~

"The relationship berween I T ratios and INRs differs shghtly between the studies because of variable sensitivities of local thromboplastins.

INR = international normalized ratio; PT = prothrombin time; AFASAK = Copenhagen Atrial Fibrillation, Aspirin, Anticoagulation study; SPAF = Stroke Prevention in Atrial Fibrillation study; BAATAF = Boston Area Anticoagulation Trial for Atrial Fibrillation.

in their responsiveness to the anticoagulant effects of warfarin, and current US thromboplastins produce lower prothrombin ratios than previous preparations. Since the responsiveness of commercial thromboplastins will vary to some extent, the optimal method for reporting the intensity of anticoagulation is the international normahzed ratio (INR). The I N R represents the FT ratio that would have been obtained if the international reference thromboplastin had been used as the reagent. A variety of clinical studies have shown that for a typical US thromboplastin, a FT ratio in the range of 1.3 to 1.5 (INR of 2.0 to 2.5) provides the same degree of protection against a variety of thromboembolic events as does more intense anticoagulation C201. In addition, lower-intensity therapy is associated with as much as a three- to fourfold reduction in both major and minor bleeding complications {20, 2 13. The prospective AF trials did not use uniform guidelines for anticoagulant intensity (Table 1). The trial with the highest intensity was the AFASAK study, which had a target INR of 2.8 to 4.2 (PTratio of 1.5 to 2.0). The lowest intensity was used in the BAATAF trial (INR of 1.5 to 2.7, PT ratio of 1.2 to 1.5). Because of uncertainty regarding the optimal dose of aspirin for prevention of thromboembolic events, aspirin doses also varied in the two trials in which randomized aspirin therapy was evaluated. The AFASAK trial used a dose of 75 mglday, while 325 mgtday was employed in the SPAF trial. Hemorrhagic Complications of Oral Anticoagulant Therapy Bleeding complications are clearly the major risk associated with anticoagulant therapy. In general, most studies reveal about a 5 to 10% chance of a bleeding episode occurring for each year of anticoagulation [22). However, the majority of anticoagulant-associated bleeding events are minor and do not produce significant morbidity. Major hemorrhage is often defined as a hemorrhage that is severe enough to require hospital-

ization, transfusion, or surgery. N o reliable estimates of the risk of major hemorrhage in chronically anticoagulated patients with AF were previously available 1221. The most serious anticoagulant-related complication is intracerebral hemorrhage. A major risk factor for this complication is excessive anticoagulation [23-251. Other risk factors for anticoagulant-associated bleeding include uncontrolled hypertension, unrecognized medical conditions, combining aspirin and anticoagulant therapy, and trauma [23, 24, 26, 27). Age over 65 has been implicated as a risk factor for anticoagulantinduced hemorrhage, although several studies documented no increase in bleeding episodes in elderly individuals who were good candidates for anticoagulation 128-3 11. Patients with significant risk factors for anticoagulant-associated bleeding were excluded from warfarin treatment in the randomized trials. Specific criteria varied between the studies but typically included coagulopathy or blood dyscrasias, any episode of hemorrhage in the previous 6 months, occult bleeding, unstable gait, uncontrolled hypertension, alcoholism, or suspicion that the patient would be unable to comply with routine follow-up and monitoring of anticoagulant therapy. Summary of Randomized Prospective Trials The Copenhagen Atrial Fibrillation, Aspirin, Anticoagulation Study The first prospective, randomized study to be completed was the Copenhagen AFASAK study [lo}. In this 2-year study, 1,007 patients were randomized into three treatment groups: (1) oral anticoagulation with warfarin, ( 2 ) aspirin at 75 mg/day, or ( 3 ) placebo. Effective randomization was achieved for all major risk factors of stroke except for age (warfarin-treated patients had a median age of 72.8 years; aspirin group, 75.1 years; placebo group, 74.6 years; p < 0.03). Since younger patients have a lower risk for stroke, this age difference might be expected to provide a slight bias in favor of warfarin treatment. The aspirin and placebo arms were double-blinded; the warfarin treatment arm was unblinded. A signlficant problem encountered in this study was that 38% of the warfarin-treated patients withdrew from the study. Most of the dropouts were attributed to the inconvenience of the required blood draws (only 7% were due to side effects of treatment). The goal for anticoagulant intensity in this study was an INR of 2.8 to 4.2 (PT ratio approximately 1.5 ro 2.0). Patients were maintained within this range for 42% of the total treatment time. However, excessively high levels (above an INR of 4.2) were only recorded 0.6% of the time. Levels below an INR of 2.4 were obtained 26% of the time. The degree of anticoagulation was

monitored at least every 4 weeks. Six percent of the warfarin-treated patients had bleeding-related side effects as compared to only 1% of the aspirin group and none of the placebo-treated patients. All bleeding episodes were nonfatal, and only 2 patients required blood transfusions (1 in the aspirin group and 1 warfarin-treated patient who was excessively anticoagulated). Forty-three percent of the warfarin-treated patients who had bleeding episodes were subsequently discovered to have an inflammatory or malignant disease in the urogenital or gastrointestinal tract. The warfarin-treated patients had significantly fewer strokes and systemic emboli, compared to either the aspirin or placebo groups. The incidence of thromboembolic complications (stroke, transient ischemic attack, and systemic embolus) was 2% per year in the warfarin-treated patients (95% confidence limits, 0.6 to 4.8%) versus 5.5% per year in both the aspirin- and placebo-treated patients (95% confidence limits, 2.9 to 9.4%) (p < 0.05). Three of the five strokes in the warfarin group occurred at times when the patients were not taking the medication (one during evaluation for hematuria, one before an elective operation, and one on the day of randomization). One of the stroke patients in the warfarin group had a fatal intracerebral hemorrhage that was associated with an INR of 3.7. N o stroke patient in the aspirin or placebo group had hemorrhage, as demonstrated by computed tomography (CT) scan; however, CT scan or autopsy results were not available in 25% of the stroke patients. Warfarin-treated patients who discontinued their medication continued to be observed for the duration of the study and did not appear to experience an excessive rate of thromboembolic complications. An intention-to-treat analysis including all three groups also revealed a significant reduction in thromboembolic events attributable to warfarin, with probability values of 0.056 (chi square) and 0.046 (likelihood ratio test) 1161. When the anticoagulation group was compared with the placebo group only, the p value in favor of warfarin was 0.025. No relationship between left atrial size and stroke was documented in this study. Patients with a history of myocardial infarction were the only subgroup found to be at increased risk for stroke [321. In summary, the Copenhagen study provided the first prospective evidence that the benefits of chronic warfarin therapy outweighed the bleeding risks in patients with NVAF. This study also provided the first prospective assessment of antiplatelet therapy in AF and failed to document stroke reduction attributable to aspirin.

Strobe Prwention in Atrial Fibrillation Study The SPAF study was a randomized multicenter treatment trial comparing warfarin or aspirin to placebo for

Neurological Progress: Albers et al: Stroke Prevention in NVAF 513

the prevention of stroke and systemic embolism in patients with nonrheumatic AF { l l]. Eligible patients must have had either constant or intermittent AF documented by electrocardiogram within the 12 months prior to enrollment. Patients who were excluded had prosthetic valves, echocardiographic evidence of mitral stenosis, or a generally recognized need for or contraindication to aspirin or anticoagulation. Eligible, consenting patients were categorized as warfarin-eligible (Group I) or warfarinineligible (Group 11). Patients with certain medical conditions such as gastrointestinal or intracranial bleeding contraindicating warfarin treatment were randomized to Group 11, as were patients who were unwilling to possibly be randomized to receive warfarin. In addition, during the initial phase of the study, age over 75 was an automatic exclusion from Group I. This age restriction was subsequently eliminated. Young patients (< 50 years) with lone AF were also excluded from Group I because of their low stroke and embolism risk. The most common reasons for randomization to Group I1 were that the patients or their physicians refused possible warfarin therapy, age over 75, and inability to obtain adequate follow-up for PTs. An analysis of vascular risk factors and risk factors for bleeding showed no apparent difference between Group I and Group I1 patients. Group I patients were randomized to receive openlabel warfarin or to aspirin or placebo in a doubleblinded fashion. Warfarin doses were adjusted to achieve a PT, using conventional North American rabbit brain thromboplastin reagents, between 1.3 and 1.8 times control values (INR of 2.0 to 3.5). The mean PT ratio was 1.45 ? 0.23 (standard deviation) with a mean warfarin dose of 4.8 f 1.9 mg daily. In both Groups I and I1 the aspirin dose was 325 mg/day, enteric coated with identical placebo. All patients were followed every 3 months. When 1,330 randomized patients had been followed for a mean of 1.3 years, the study was interrupted by the monitoring committee because a significant benefit of active (warfarin or aspirin) therapy over placebo was apparent in Group I. At that point, 627 patients (47%) had been assigned to Group I and 703 to Group 11. Randomized patients had a mean age of 67 years, 7 1% were men, and about half (52%) had a history of hypertension. Most (66%) had constant AF. Angina pectoris was present in lo%, congestive heart failure in 19%, and prior myocardial infarction in 8%. The rate of primary events (ischemic stroke and systemic embolism) was substantially reduced in those treated with warfarin (2.3% per year) compared to placebo (7.4% per year) @ = 0.01; risk reduction, 67%; 95% confidence interval, 27 to 85%). Of 6 patients in the warfarin group who had ischemic strokes, 2 had previously withdrawn from the study and 2 had 514 Annals of Neurology Vol 30 No 4 October 1991

stopped warfarin 5 days prior to the stroke and had normal PTs. In all patients (i.e., Groups I and I1 combined) assigned to receive aspirin, there was a lower rate of primary events (3.6% per year) than in those given placebo (6.3% per year) (p = 0.02; risk reduction, 42%; 95% confidence interval, 9 to 63%). Regarding the 26 primary events in the patients who received aspirin, 22 of them had taken aspirin within 7 days of the event. Subgroup analysis revealed an apparent lack of aspirin benefit in patients older than 75 years. Major bleeding complications occurred in 1.593, 1.496, and 1.6% per year of patients assigned to warfarin, aspirin, and placebo, respectively (Groups I and I1 combined). An end-point adjudication committee reviewed each event with all clinical data purged of reference to treatment. Two-thirds of the ischemic strokes were judged to be cardioembolic in origin. Too few events occurred in the warfarin- and aspirin-treated patients of Group I (warfarin-eligible) to assess the relative benefit of aspirin versus warfarin. The study continues as a randomized comparison of warfarin to aspirin (SPAF 11). Boston Area Anticoagulation Trial for Atrial Fibrillation

The BAATAF study was an unblinded, randomized, controlled trial of long-term, low-dose warfarin therapy in patients with nonrheumatic AF [12]. Anticoagulation was monitored by a central center with a prothrombin range target of 1.2 to 1.5 times control values (INR of 1.5 to 2.7). PTs were monitored at least every 3 weeks. Control patients were allowed to take aspirin at the discretion of their personal physician. Aspirin use was not randomized but carefully monitored. All neurologic episodes were reviewed by a blinded, endpoint committee. A total of 420 patients (212 in the warfarin group and 208 in the control group) with a mean age of 68 years entered the trial and were followed an average of 2.2 years. Most patients had chronic AF; 17% had paroxysmal AF. PTs were in the target range 83% of the time and 90% of the patients assigned to receive warfarin remained on treatment. Ischemic stroke occurred in 13 patients in the control group (incidence, 2.98% per year) as compared to 2 in the warfarin group (incidence, 0.41% per year). This represents a risk reduction of 86% (95% confidence interval, 51% to 9696, p = 0.0022). Of all the patient-years in the control group, 46% were from patients taking aspirin regularly. Eight of the 13 strokes in the control group occurred in patients taking aspirin, 7 of those were taking at least 325 mg/day (incidence of stroke, 3.99% per year). The death rate was lower in the warfarin group (2.25% per year) than the control group (5.97% per year). Two fatal hemorrhages occurred, a pre-

Table 2. Efficao of WarJarin far Prevention of Stroke (Intention-to-Treat Analysis)”

AFASAK SPAF BAATAF Totalb Control Person-years Strokes

Table 3. Efficacy of Warfarin for Prevention of Systemic Non-Central Nervous System Emboli (Intention-to-Treat Analysis) a

AFASAK SPAF BAATAF Totalb

4 13 19 4.6

Strokeiyr (s) Warfarin Person-years 4 12 Strokes 8 Stroke/yr (9%) 1.9

244 17 7.0 260

6 2.3

435 13 3.0 487 2 0.4

1,092 49 4.5

1,159 16 1.4

’Strokes represent all strokes regardless of suspected etiology. Transient ischemic attacks, systemic emboli, and intracranial hemorrhages are not included. Control represents placebo in all studies except BAATAF where 46% of the “control” patients received aspirin and 545% received no treatment. Strokeiyr represents stroke events per 100 person-years. SPAF data are from Group I only. See Table 1 for abbreviation key. ‘69% Reduction in risk of stroke;p < 0.001 by chi-square analysis; 95% confidence interval, 48 to 82%.

sumed intracranial hemorrhage in a patient taking warfarin and a pulmonary hemorrhage in the control group. One patient in the warfarin group had a major nonfatal gastrointestinal hemorrhage that required transfusion. Minor bleeding occurred in 38 patients in the warfarin group, with transfusion required in 2, and in 21 patients in the control group, with transfusion required in 1 patient. Age and mitral annular calcification were associated with increased risk for stroke whereas AF without clinical heart disease was associated with a lower risk. Of the 2 strokes in the warfarin group, one occurred with a PT ratio of 1.2 1 and one with a PT ratio of 1.18. Clinical evidence favored an embolic mechanism in 11 of the 15 definite strokes. In the remaining 4 patients, there was evidence of other causes (carotid stenosis in 1 control patient, possible small-vessel disease in 2 in the control group and 1 in the warfarin group). Patients with intermittent and sustained AF had similar risks. Results of the BAATAF study demonstrated that long-term, low-dose warfarin therapy is both effective and safe with careful monitoring. Efficacy was not demonstrated for aspirin in a nonrandomized assessment.

Conclusions The studies reviewed indicate that chronic anticoagulation with warfarin can reduce the risk of stroke (Table 2) and systemic embolism (Table 3 ) in large populations of patients with NVAF. Summation of the data from the intention-to-treat analysis of all three studies reveals a 69% reduction in stroke, from 4.5% per year to 1.4% per year. The highest estimate of warfarin’s preventive efficacy (86%) was found in the BAATAF study, where the high rate of compliance negated differences between an intention-to-treat and on-treatment analysis. In the other studies, the vast majority of

Control Person-years Systemic emboli Systemic emboliiyr (z) Warfarin Person-years Systemic emboli Systemic ernboliiyr (%)

413 3 0.73 4 12 1 0.24

244 1

0.41 260 0

0.00

435 lC 0.23

1,092

487 0 0.00

1,159 1 0.09

5 0.46

“Systemic emboliiyr represent systemic emboli per 100 personyears. Control represents placebo in all studies except BAATAF where 46% of the “control” patients received aspirin and 54% received no treatment. SPAF dara are from Group I. See Table 1 for abbreviation key. ’81% Risk reduction, not significant by chi-square analysis. ‘“Possible” systemic embolus (despite full evaluation it was unclear whether this event represented a thrombus in situ or an embolus).

Table 4. EfJicacy of Warfarin far Prevention of Stroke (On-Treatment Analysisia

AFASAK SPAF BAATAF Totalb Control

4 13 Person-years 19 Strokes Stroke/yr 4.6 Warfarin Therapeutic-years 105 1 Strokes 1.0 Stroke/yr (%)

(s)

244 435 17 13 3.0 7.0 168 369 2 2 1.2 0.5

1,092 49

4.5 642 5 0.8

’Therapeutic-years represent an estimate of the amount of time warfarin-treated patients were within the desired intensity for anticoagulation. Strokes represent stroke events that occurred while patients were anticoagulated within the therapeutic range. The “therapeutic range” is the target range for each study as indicated in Table 1. All strokes are included regardless of suspected etiology. Transient ischemic attacks, systemic emboli, and intracranial hemorrhages are not included. Control represents placebo in all studies except BAATAF where 46% of the “control” patients received aspirin and >4% received no treatment. Strokeiyr represents stroke events per 100 person-years. SPAF data are from Group I only. See Table 1 for abbreviation key. ’83% Risk reduction; p < 0.001 by chi-square analysis; 95% confidence interval, 61-92%.

strokes in the warfarin-treated patients occurred when patients were not receiving treatment or were significantly underanticoagulated. A secondary analysis of stroke events occurring during adequate anticoagulation indicates a stroke reduction of 83% (Table 4). There is no evidence that higher-intensity anticoagulation provided greater stroke reduction than did lowintensity therapy. Anticoagulation was effective for preventing infarcts of all severities (Table 5). In the s m a l l number of anti-

Neurological Progress: Albers e t

al:

Stroke Prevention i n NVAF 515

Table 5 . Comparison of Severity of Intracranial Events between Wa$arin-Treated and Control Patients (Intention-to-TreatAnalysis)a

Mild Warfarin Control Moderate/severe Warfarin Control Fatal Warfarin Control

Table 7 . Effitaary of Aspirin for Prevention of Stroke (Intention-to-Treat Analysis)“

AFASAK

SPAF

BAATAF

3

0

8

7

5 12

4

23 9 23

5

2

2

8

7

8

1 4

1 0

1

1

Total

3 5

‘Intracranial events include all strokes and intracranial hemorrhages. Transient ischemic attacks and systemic emboli are not included. Control represents placebo in all studies except BAATAF where 46% of the “control” patients received aspirin and 54% received no treatment. Mild represents minimal or no disability. Moderateisevere represents moderate to severe disability. SPAF data are from Group I only. See Table 1 for abbreviation key.

Table 6. Bleeding Rates in Prospective Atrial Fibrillation Trials”

AFASAK SPAF Intracere bra1 hemorrhage Warfarin Control

Major bleeding Warfarin Control Minor bleeding Warfarin Control

BAATAF Total

l(0.4) 0 (0.0)

1 (0.4) 1 (0.4)

1 (0.2) 0 (0.0)

3 (0.3) 1 (0.1)

1 (0.4) 0 (0.0)

3 (1.2) 3 (1.2)

5 (1.0) 7 (1.6)

9 (0.8) 10 (0.9)

20 (8.0) 0 (0.0)

4 (1.5) 1 (0.4)

34 (7.0)

58 (5.0)

15 (3.5)

16 (1.5)

aAll data are presented on an intent-to-treat basis except the AFASAK trial in which data represent treatment received. Control represents placebo in all studies except BAATAF where 46% of the “control” patients received aspirin and 54% received no treatment. Numbers in parentheses represent bleeding events per 100 patientyears. Major bleeding is defined as bleeding severe enough to require hospitalization, blood transfusion, or surgery. The intracerebral hemorrhage in the BAATAF study was suspected on the basis of clinical data-no CT or autopsy was available. SPAF data are from Group I only. See Table 1 for abbreviation key.

coagulated patients who had strokes, there was no evidence that the ischemic strokes were more severe or more likely to be hemorrhagic. One warfarin-treated patient in each study had an intracerebral hemorrhage (Table 6). The rate of major bleeding or intracranial hemorrhage was nearly identical in warfarin-treated patients and in controls; minor bleeding was about three times more frequent in warfarin-treated patients (see Table 6). The role of aspirin for stroke prevention in AF is less clear as one study, AFASAK, found no significant benefit, while SPAF documented significant protection (Table 7). The reason for the apparent contradiction

516 Annals of Neurology Vol 30 No 4 October 1991

Placebo Person-years Strokes Strokeiyr (ss6) Aspirin Person-years Strokes Strokeiyr (%)

AFASAK

SPAF

Totalb

413 19 4.6

731 42 5.8

1,144 61 5.3

413 16 3.9

720 23 3.2

1,133 39 3.4

‘Strokes represent all strokes regardless of suspected etiology. Transient ischemic attacks, systemic emboli, and intracranial hemorrhages are not included. Stroke/yr represents stroke events per 100 patientyears. SPAF data are from Group I d d Group I1 combined. The aspirin dose was 75 mgiday in the AFASAK study and 325 mgiday in the SPAF study. b355E Risk reduction; p = 0.03 by chi-square analysis; 95% confidence interval, 5-5696.

between these two similar studies is not entirely clear. One possible explanation is that the average age (74 years) of the patients in the AFASAK trial was higher than that of the SPAF patients (67 years). This age difference could account for the discrepancy if aspirin is more effective for younger patients, as suggested by subgroup analysis of the SPAF data. Alternatively, the higher dose of aspirin used in the SPAF study (325 mg/day) may be more effective than the lower dose (75 mg/day) used in the AFASAK study. The nonrandomized analysis of aspirin in the BAATAF study failed to suggest any aspirin benefit; the observed stroke rate in patients receiving aspirin was eight times that of those taking warfarin. The ongoing SPAF I1 trial may help clarify the role of aspirin. The currently available data favor the use of chronic warfarin therapy for stroke prophylaxis in patients with AF. However, this does not imply that routine anticoagulation of all patients with AF is warranted. Although the prospective studies demonstrated benefit for large groups of patients with AF, it would not necessarily be expected that all subgroups would benefit. For example, young patients with lone AF have an expected stroke rate of less than 0.5% per year; therefore, the risk of major bleeding associated with chronic warfarin therapy may negate the expected benefit. Aspirin therapy appears to be a logical alternative for these patients. In addition, patients who have risk factors that increase their risk of anticoagulant-associated bleeding would be less likely to benefit from warfarin therapy. Aspirin may be a better choice for these patients as well. Unfortunately, neither previous studies nor these prospective trials were able to clearly identify echocardiographic risk factors that would allow accurate identification of patients who are most likely to have strokes.

For example, preliminary observations that left atrial size is not a reliable predictor of stroke risk in AF [ 7 , 16, 33-36] were confirmed in the prospective studies. Because of the inability to clearly identify subgoups at high risk for stroke, large numbers of patients will require treatment to prevent stroke in a few patients per year. Potentially, transesophageal echocardiography, which was not routinely included in the prospective trials, may help clarify which patients are actually at the highest risk for stroke, This technique has a much higher yield than transthoracic echocardiography for identification of intracardiac thrombi in patients with AF as well as documenting slow blood flow in the atrium, which may predispose to thrombus formation C37, 38).

Other pertinent issues, such as at what age benefit from anticoagulation would be expected in young patients with lone or paroxysmal AF, remain to be answered. Very few thrornboembolic events occurred in these populations, making risk-versus-benefit analysis difficult. In addition, since about one-third of the strokes that occurred in these studies were clinically judged to be noncardioembolic, any correlation between presumed stroke etiology and treament effect will also be important. It is hoped that combining data from multiple similar studies will clarify the role of warfarin and aspirin for these subpopulations and a collaborative meta-analysis is currently underway.

Recommendations Although anticoagulation decisions axe always based on clinical judgment, the following guidelines are based on the currently available data:

1. The benefits of chronic warfarin therapy exceed the risks for the majority of patients with NVAF, provided they are good candidates for anticoagulation. 2. Low-dose anticoagulation (INR of 1.5 to 2.7, PT ratio of 1.2 to 1.5) probably provides equivalent efficacy and a lower incidence of bleeding complications than does higher-intensity anticoagulation. Careful monitoring of anticoagulant intensity to avoid excessive anticoagulation is necessary. 3. Patients who are not good candidates for oral anticoagulation or who are opposed to anticoagulation should consider aspirin at a dose of 325 mglday until further data are available. 4. For patients less than 60 years old with lone or paroxysmal AF, aspirin at a dose of 325 mg/day rather than warfarin should be considered. The authors thank Kathryn Muller for editorial assistance and Mildred Bradke for help in preparing this manuscript.

References 1. Cerebral Embolism Task Force. Cardiogenic brain embolism.

Arch Neurol 1986;43:7 1-84 2. Wolf PA, Dawber TR, Thomas HE, Kannel WB. Epidemiologic assessment of chronic atrial fibrillation and risk of stroke: the Framingham study. Neurology 1978;28:973-977 3. D u n M, Alexander J, deSilva R, Hildner F. Antithrombotic rherapy in atrial fibrillation. Chest 1989;95:118S-l25s 4. Roy D, Marchand E, Gagne P, et al. Usefulness of anticoagulant therapy in the prevention of embolic complications of atrial fibrillation. Am Heart J 1986;112:1139-1143 5. Kitchens JM, Flegel KM. Atrial fibrillation, stroke and anticoagulation: what is to be done? J Gen Intern Med 1986;1:126-129 6. Halperin JL, Hart RG. Atrial fibrillation and stroke: new ideas, persisting dilemmas. Stroke 1988;19:937-94 I 7. Cerebral Embolism Task Force. Cardiogenic brain embolism. Arch Neurol 1989;46:727-743 8. Stein B, Fuscer V, Halperin JL, Chesebro JH. Antithrombotic therapy in cardiac disease: an emerging approach based on pathogenesis and risk. Circulation 1989;80:1501-15 13 9. Levine HJ, Pauker SG, Salzman EW. Antithrombotic therapy in valvular heart disease. Chest 1989;95S:98S-l06S 10. Petersen P, Goddredsen J, Boysen G , et al. Placebo-controlled, randomized trial of warfarin and mpirin for prevention of thromboembolic complications in chronic atrial fibrillation: The Copenhagen AFASAK study. Lancet 1989;1:175-179 11. The Stroke Prevention in Atrial Fibrillation Investigators. Preliminary report of the stroke prevention in atrial fibrillation study. N Engl J Med 1990;322:863-868 12. The Stroke Prevention in Atrial Fibrillation Investigators. The stroke prevention in atrial fibrillation study: final results. Circulation 1991;84:527-539 13. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. N Engl J Med 1990;323:1505-1511 14. Brand FN, Abbott RD,Kannel WB, Wolf PA. Characteristics and prognosis of lone atrial fibrillation. JAMA 1985;254: 3449-3453 15. Kopecky SL, Gerah BJ, McGoon MD, et al. The natural history of lone atrial fibrillation. N Engl J Med 1987;317:669-674 16. Petersen P. Thromboembolic complications in atrial fibrillation. Stroke 1990;21:4-13 17. Sherman DG, Goldman L, Whiting RR, et al. Thromboembolism in patients with atrial fibrillation. Arch Neurol 1984;41: 708-710 18. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation: a major contributor to stroke in the elderly: the Framingham study. Arch Intern Med 1987;147:1561- 1564 19. Flegel KM, Hanley J. Risk factors for stroke and other embolic events in patients with nonrheumaric atrial fibrillation. Stroke 1989;20:1000-1004 20. Hirsh J, Poller L, Deykin D, et al. Optimal therapeutic range for oral anticoagulants. Chest 1989;95S:5S-lOS 2 1. Turpie AGG, Gunstensen J, Hirsh J, et al. Randomized comparison of two intensities of oral anticoagulant therapy after tissue heart valve replacement. Lancet 1988;1:1242-1245 22. Levine MN, Rashkob G, Hirsh J. Hemorrhagic complications of long-term anticoagulant therapy. Chest 1989;95S:26S36s 23. Kase CS, Robinson RK,Stein RW, et al. Anticoagulant-relaced intracerebral hemorrhage. Neurology 1985;35:943-948 24. Wintzen AR, deJonge H, Lodger EA, Bots GTAM. The risk of intracerebral hemorrhage during oral anticoagulant treatment: a population study. Ann Neurol 1984;16:553-558 25. Albers GW. Intensity of anticoagulant treatment and risk of intracerebral hematoma. Stroke 1990;21:1758

Neurological Progress: Albers et al: Stroke Prevention in NVAF 517

26. Coon WW, Willis WP. Hemorrhagic complications of anticoag27.

28.

29.

30.

31. 32.

ulant therapy. Arch Intern Med 1974;133:386-392 Errichetti AM, Holden A, Ansell J. Management of oral anticoagulant therapy: experience with an anticoagulation clinic. Arch Intern Med 1984;144:1966-1968 Whisnant JP, Cartlidge NE, Elveback LR. Carotid and vertebral basilar transient ischemic attacks: effects of anticoagulants, hypertension and cardiac disorders on survival and stroke occurrence-a population study. Ann Neurol 1978;3:107-115 Forfar JC. A 7-year analysis of haemorrhage in patients on long-term anticoagulant treatment. Br Heart J 1979;42:128132 Sixty Plus Reinfarction Study Research Group. Risks of long term oral anticoagulant therapy in elderly parients after myocardial infarction. Lancet 1982;1:64-68 Petty GW, Lennihan L, Mohr JP, er al. Complications of longterm anticoagulation. Ann Neurol 1988;23:570-574 Petersen P, Kastrup J, Helweg-Larsen S, et al. Risk factors for thromboembolic complications in chronic atrial fibrillation: the

518 Annals of Neurology Vol 30 No 4

October 1091

33.

34. 35.

36.

37.

38.

Copenhagen AFASAK study. Arch Intern Med 1990;150 819-821 Wiener I. Clinical and echocardiographic correlates of systemic embolization in nonrheumatic atrial fibrillation. Am J Cardiol 1987;59: 177 Tegeler CH, Hart RG. Atrial size, atrial fibrillation and stroke. Ann Neurol 1987;21:715-316 Aronow WS, Gustein H, Hsieh FY.Risk factors for rhromboernbolic stroke in elderly patients with chronic atrial fibrillation. Am J Cardiol 1989;63:366-367 D’Olhaberriague L, Hernandez-Vidal A, Molina L, et al. A prospective study of atrial fibrillation and stroke. Stroke 1989;20: 1648-1652 de Belder MA, Tourikis L, Leech G, Camm AJ. Spontaneous contrast echos are markers of thromboembolic risk in patients with atrial fibrillation. Circulation 1989;80(SuppI 1I):II-1 Malone SA, Palac RT, Imus RL, et al. Prevalence of left atrial thrombi in symptomatic versus asymptomatic patients with nonvalvular atrial fibrillation. Circulation 1989;8O(Suppl II):II-1