Antithrombotic Therapy in Atrial Fibrillation Andreas Laupacis, M.D., M.Sc., Chairman Gregory Albers, M. D. Maroin Dunn, M.D., F.C.C.P. William Feinberg, M. D.
,t trial fibrillation (AF) is the most common cardiac
.t1 disorder predisposing to systemic embolism. The
overall prevalence of AF in the Framingham cohort was 2.2 percent in men and 1. 7 percent in women. 1 The prevalence rose with age, from approximately 0.2 percent for those 25 to 34 years of age to approximately 3.0 percent for those 55 to 64 years of age. In a community-based study in Rochester, Minn, 16. l percent of men and 12.2 percent of women older than 75 years of age had AF. 2 In the past, the disorder most commonly associated with AF was rheumatic mitral valvular disease. However, heart failure and hypertensive cardiovascular disease are now the conditions most commonly associated with AF. 1-3 The prevalence of idiopathic or lone atrial fibrillation, defined as the absence of cardiopulmonary disease or other precipitating causes, varies considerably among studies from approximately 3 percent in Rochester, Minn 2 to approximately 30 percent in Iceland. 3 In this section the indications for antithrombotic therapy will be considered in those with (1) nonvalvular AF (defined as patients who do not have rheumatic mitral valvular disease), (2) valvular heart disease, and (3) miscellaneous conditions. NONVALVULAR ATRIAL FIBRILLATION
Four level I and one level II studies assessing antithrombotic therapy as primary prevention in nonvalvular AF have recently been published. These are the Atrial Fibrillation, Aspirin, Anticoagulation study from Copenhagen, Denmark (AFASAK), 4 the Stroke Prevention in Atrial Fibrillation study from the United States (SPAF), 5 the Boston Area Anticoagulation Trial for Atrial Fibrillation (BAATAF), 6 the Canadian Atrial Fibrillation Anticoagulation study (CAFA), 7 and the Stroke Prevention in Nonrheumatic Atrial Fibrillation study (SPINAF). 8 Because these studies provide the highest quality evidence regarding antithrombotic therapy in AF, they will be discussed in some detail. All five studies compared warfarin with either placebo or control, and two of them also had an aspirin arm. All studies terminated prematurely. The AFASAK, SPAF, BAATAF, and SPINAF studies were stopped because interim analyses of each study convinced the investigators that the evidence for the 428$
benefit of warfarin obtained in their study was sufficiently compelling to make continued randomization to the control group unethical. The SPAF investigators also found a benefit associated with aspirin use. The CAFA investigators did not perform any interim analyses, but stopped their trial prematurely because they felt that the published results of the other studies had established the efficacy of warfarin. 9 The design and results of the five studies are presented below.
Design All studies were randomized controlled trials comparing warfarin with a control arm. The AFASAK and SPAF studies each had an aspirin arm as well. In the SPAF study, patients were categorized as either warfarin-eligible (group 1) or warfarin-ineligible (group 2). Group 1 patients were randomized equally to warfarin, aspirin, or placebo. Group 2 patients were randomized to aspirin or placebo. In the CAFA and SPINAF studies, warfarin administration was double-blind. The SPAF and AFASAK studies administered aspirin and placebo in a double-blind fashion, but warfarin administration was open labelled. In the BAATAF investigation, the control group was not given warfarin but could choose to take aspirin (46 percent of the patient years in the control group were contributed by patients who were taking aspirin regularly).
Intervention The target INR in warfarin-treated patients varied among studies (Table 1). The aspirin dose was 75 mg a day in the AFASAK investigation and 325 mg a day in the SPAF study.
Patient Characteristics The characteristics of the patients in the placebo or control groups are shown in Table 2. Many patients had hypertension, coronary artery disease, or heart failure. The AFASAK patients were, on the average, older and more likely to have a history of heart failure, and none of them had intermittent AF.
Outcome Events The primary event outcomes in each study are listed in Table 1. All studies considered stroke a primary event. Some of the studies also included non-central nervous system (CNS) systemic emboli, transient Antithrombotic Therapy In Atrial Fibrillation (Lampacis et al)
Table I-Study Summaries
AFASAK SPAF BAATAF CAFA SPIN AF
Total Number of Patients
Mean Follow-Up, yr
Target INR
1,007 1,330 420
1.2 1.3 2.2 1.3 1.8
2.8-4.2 2.0-3.5 1.5-2.7 2.0-3.0 1.4-2.8
383
52.5
Primary Outcome Measure* S, SE, TIA, ICB S, SE
s
S, SE, ICB, FB
s
*S =stroke; SE= non-CNS systemic em bolus; TIA= transient ischemic attack; ICB = intracranial bleed; FB =fatal bleed.
ischemic attacks, intracranial bleeding, and fatal bleeding as primary events. The exact definition of a major bleed varied slightly among studies, but in general, a bleed was classified as major if transfusion was required, if the patient was hospitalized, or if the bleed occurred in a critical anatomic location (eg, intracranial, perispinal). The criteria used by the BAATAF investigators were more stringent: intracranial bleeds, fatal bleeds, or bleeds leading to transfusion of four or more units of blood within 48 h. The primary analysis was based upon the intention to treat principle in the SPAF, BAATAF, and SPINAF studies. In the primary analysis of the AFASAK study, events were counted until patients discontinued their study medication (the withdrawal rate was 38 percent in warfarin-treated individuals, 13 percent in patients taking aspirin, and 15 percent in those receiving placebo). The CAFA study included all events that occurred within 28 days of permanent discontinuation of the study medication (early permanent discontinuation occurred in 26 percent of warfarin and 23 percent of placebo-treated patients).
aspirin provided a 42 percent relative risk reduction in primary outcome events compared with placebo, while in the AFASAK study, there was no benefit provided by using aspirin. However, the confidence intervals surrounding the estimates of efficacy in each study overlap each other and are consistent with the benefit of aspirin. The percentage of strokes classified as moderate, severe or fatal was 64 percent in AFASAK, 46 percent in SPAF, 73 percent in BAATAF, 43 percent in CAFA, and 61 percent in SPINAF. Warfarin was effective in preventing strokes of all severities. There was no evidence that the strokes occurring in patients receiving anticoagulants were more severe. There was no statistically significant increase in major bleeding events in warfarin- or aspirin-treated patients (Table 3) in any study. In the AFASAK study, there was a statistically significant decrease in vascular deaths in the warfarintreated patients (0.9 percent warfarin, 3.6 percent aspirin, 4.5 percent placebo: p
,t trial fibrillation (AF) is the most common cardiac
.t1 disorder predisposing to systemic embolism. The
overall prevalence of AF in the Framingham cohort was 2.2 percent in men and 1. 7 percent in women. 1 The prevalence rose with age, from approximately 0.2 percent for those 25 to 34 years of age to approximately 3.0 percent for those 55 to 64 years of age. In a community-based study in Rochester, Minn, 16. l percent of men and 12.2 percent of women older than 75 years of age had AF. 2 In the past, the disorder most commonly associated with AF was rheumatic mitral valvular disease. However, heart failure and hypertensive cardiovascular disease are now the conditions most commonly associated with AF. 1-3 The prevalence of idiopathic or lone atrial fibrillation, defined as the absence of cardiopulmonary disease or other precipitating causes, varies considerably among studies from approximately 3 percent in Rochester, Minn 2 to approximately 30 percent in Iceland. 3 In this section the indications for antithrombotic therapy will be considered in those with (1) nonvalvular AF (defined as patients who do not have rheumatic mitral valvular disease), (2) valvular heart disease, and (3) miscellaneous conditions. NONVALVULAR ATRIAL FIBRILLATION
Four level I and one level II studies assessing antithrombotic therapy as primary prevention in nonvalvular AF have recently been published. These are the Atrial Fibrillation, Aspirin, Anticoagulation study from Copenhagen, Denmark (AFASAK), 4 the Stroke Prevention in Atrial Fibrillation study from the United States (SPAF), 5 the Boston Area Anticoagulation Trial for Atrial Fibrillation (BAATAF), 6 the Canadian Atrial Fibrillation Anticoagulation study (CAFA), 7 and the Stroke Prevention in Nonrheumatic Atrial Fibrillation study (SPINAF). 8 Because these studies provide the highest quality evidence regarding antithrombotic therapy in AF, they will be discussed in some detail. All five studies compared warfarin with either placebo or control, and two of them also had an aspirin arm. All studies terminated prematurely. The AFASAK, SPAF, BAATAF, and SPINAF studies were stopped because interim analyses of each study convinced the investigators that the evidence for the 428$
benefit of warfarin obtained in their study was sufficiently compelling to make continued randomization to the control group unethical. The SPAF investigators also found a benefit associated with aspirin use. The CAFA investigators did not perform any interim analyses, but stopped their trial prematurely because they felt that the published results of the other studies had established the efficacy of warfarin. 9 The design and results of the five studies are presented below.
Design All studies were randomized controlled trials comparing warfarin with a control arm. The AFASAK and SPAF studies each had an aspirin arm as well. In the SPAF study, patients were categorized as either warfarin-eligible (group 1) or warfarin-ineligible (group 2). Group 1 patients were randomized equally to warfarin, aspirin, or placebo. Group 2 patients were randomized to aspirin or placebo. In the CAFA and SPINAF studies, warfarin administration was double-blind. The SPAF and AFASAK studies administered aspirin and placebo in a double-blind fashion, but warfarin administration was open labelled. In the BAATAF investigation, the control group was not given warfarin but could choose to take aspirin (46 percent of the patient years in the control group were contributed by patients who were taking aspirin regularly).
Intervention The target INR in warfarin-treated patients varied among studies (Table 1). The aspirin dose was 75 mg a day in the AFASAK investigation and 325 mg a day in the SPAF study.
Patient Characteristics The characteristics of the patients in the placebo or control groups are shown in Table 2. Many patients had hypertension, coronary artery disease, or heart failure. The AFASAK patients were, on the average, older and more likely to have a history of heart failure, and none of them had intermittent AF.
Outcome Events The primary event outcomes in each study are listed in Table 1. All studies considered stroke a primary event. Some of the studies also included non-central nervous system (CNS) systemic emboli, transient Antithrombotic Therapy In Atrial Fibrillation (Lampacis et al)
Table I-Study Summaries
AFASAK SPAF BAATAF CAFA SPIN AF
Total Number of Patients
Mean Follow-Up, yr
Target INR
1,007 1,330 420
1.2 1.3 2.2 1.3 1.8
2.8-4.2 2.0-3.5 1.5-2.7 2.0-3.0 1.4-2.8
383
52.5
Primary Outcome Measure* S, SE, TIA, ICB S, SE
s
S, SE, ICB, FB
s
*S =stroke; SE= non-CNS systemic em bolus; TIA= transient ischemic attack; ICB = intracranial bleed; FB =fatal bleed.
ischemic attacks, intracranial bleeding, and fatal bleeding as primary events. The exact definition of a major bleed varied slightly among studies, but in general, a bleed was classified as major if transfusion was required, if the patient was hospitalized, or if the bleed occurred in a critical anatomic location (eg, intracranial, perispinal). The criteria used by the BAATAF investigators were more stringent: intracranial bleeds, fatal bleeds, or bleeds leading to transfusion of four or more units of blood within 48 h. The primary analysis was based upon the intention to treat principle in the SPAF, BAATAF, and SPINAF studies. In the primary analysis of the AFASAK study, events were counted until patients discontinued their study medication (the withdrawal rate was 38 percent in warfarin-treated individuals, 13 percent in patients taking aspirin, and 15 percent in those receiving placebo). The CAFA study included all events that occurred within 28 days of permanent discontinuation of the study medication (early permanent discontinuation occurred in 26 percent of warfarin and 23 percent of placebo-treated patients).
aspirin provided a 42 percent relative risk reduction in primary outcome events compared with placebo, while in the AFASAK study, there was no benefit provided by using aspirin. However, the confidence intervals surrounding the estimates of efficacy in each study overlap each other and are consistent with the benefit of aspirin. The percentage of strokes classified as moderate, severe or fatal was 64 percent in AFASAK, 46 percent in SPAF, 73 percent in BAATAF, 43 percent in CAFA, and 61 percent in SPINAF. Warfarin was effective in preventing strokes of all severities. There was no evidence that the strokes occurring in patients receiving anticoagulants were more severe. There was no statistically significant increase in major bleeding events in warfarin- or aspirin-treated patients (Table 3) in any study. In the AFASAK study, there was a statistically significant decrease in vascular deaths in the warfarintreated patients (0.9 percent warfarin, 3.6 percent aspirin, 4.5 percent placebo: p
