- Email: [email protected]
Atrial fibrillation, anticoagulation, and stroke
Atrial Joseph Morley,
Fibrillation, Anticoagulation, and Stroke MD, Roger Marinchak,
MD, Seth J. Rials, MD, PhD, and Peter Kowey,
There is a demonstrated statistical association between atrial fibrillcrtion, rheumatic valvular disease, and embolic stroke. This article assesses the results of 6 major clinical trials (AFASAK, BAATAF, SPINAF, SPAF [parts I and II], CAFA and EAFTA-see text for trial names). Multivariate analysis revealed 4 independent clinical features that identified patients with atrial fibrillation at an increased risk for stroke: hypertension, increasing age, previous transient ischemic attack, and diabetes mellitus. Without anticoagulation therapy, patients with any of these risk factors had a 4% annual risk of stroke. Patients with
MD
cardiac disorders such as congestive heart failure and coronary artery disease have a stroke rate 3 times higher than patients without any risk factors; patients with atrial fibrillation but no concomitant risk factors or structuml heart disease seemed to have little concomitant risk for stroke. Meta-analysis revealed a 64% reduction of risk for stroke in patients treated with warfarin, as compared with placebo. The value of war-fat-in thempy in patients >75 years old is less clear because of a high risk of hemorrhagic complications. (Am J Cardioll996; 77:3BAaA)
A
trial fibrillation is one of the most common agonist, pericarditis, pulmonary embolism, and the arrhythmias seen in clinical practice, and is use of cholinergic drugs.jJj the primary cardiovascular disorder predisEmbolic stroke, a frequent consequence of atria1 posing patients to systemic embolization.’ Accord- fibrillation, results in death or severe neurologic ing to the Framingham Heart Study,’ atria1 fibrilladeficit in 50-70% of episodes.’ In addition to its tion has a prevalence of 4% in the adult population, devastating morbidity and mortality, the cost of which translates into > 1 million cases in the treating patients with cmbolic stroke in the United United States each year. The incidence of atria1 States in 1993 reached $18 billion.7 Although fibrillation increases with age; it is seen in < 1% of various studies have demonstrated a 5-fold inthe 40-65year-old group, in 2-5% of the M-74creased risk of stroke in nonrheumatic atria1 librilyear-old group, and > 5% of patients > 75 years.” lation, risk is highly dependent on the concomitant Approximately 50% of patients with atria1 tibrillacardiac disease. In the Framingham Heart Study, tion in the United States are >75 years old. The patients with lone atria1 fibrillation <60 years old most common cause of atrial fibrillation is hypertenhad no increased risk of cmbolic stroke. Yet, sion, but because of the high prevalence of hypernonrheumatic atria1 fibrillation in patients with tension in the general population it is not a statistically differentiating risk factor. In contrast, hypertension, recent congestive failure, or previous congestive heart failure and rheumatic heart dis- thromboembolism was associated with an inease, although less prevalent, have a stronger creased risk for stroke of > 7% per year.8,9Atria1 association with risk of atria1 fibrillation.4 The fibrillation is responsible for 7-310/o of all strokes in Framingham Heart Study identified left atrial en- patients > 60 years old.2 In addition, patients with largement, increased left ventricular wall thick- chronic atria1 fibrillation but no apparent evidence ness, and decreased left ventricular shortening of embolic stroke have a high incidence of abnorfraction as independent risk factors for atria1 mal computed tomography scans, suggesting silent fibrillation. Extracardiac risk factors associated cerebral infarctions.lO The incidence of stroke in paroxysmal atrial with atria1 fibrillation include hypertension, diabetes mellitus, systemic illness, pneumonia, chronic fibrillation has been clarified by a combined analyobstructive lung disease, electrolyte disturbance, sis of data from the 5 mcgatrials on atria1 fibrillaalcohol intoxication, use of theophylline or beta tion, stroke, and anticoagulation.” This analysis indicates that paroxysmal and chronic atria1 fibrillation have a similar risk for embolic stroke, regardFrom the Division of Cardiovascular Diseases, The Lankenau Hospital less of the time spent in atria1 fibrillation. This and Medical Research Center, Wynnewood, Pennsylvania, and The contradicts data from Framingham, which showed Jefferson Medical College of Thomos Jefferson University, Philadelphia, Pennsylvania. men with chronic atria1 fibrillation had an annual Address for reprints: Peter R. Kowey, MD, The Lonkenau Hospital, stroke rate of 5.4%, whereas for paroxysmal atria1 Medical Office Building East, Suite 556, 100 Lancaster Avenue, fibrillation it was only 1.3%. In fact, 3 other studies Wynnewood, Pennsylvania 19096. 38A
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have reported an even lower incidence of stroke in paroxysmal atria1 fibrillation.r2-l4 Atria1 fibrillation is an arrhythmia characterized by an electrical and mechanical abnormality that predisposes to blood stasis and subsequent thrombi formation in the atria. Under certain circumstances, atria1 fibrillation can lead to hemodynamic compromise secondary to loss of atria1 kick.lS In addition, atria1 fibrillation causes an increase in symptomatic distress in many patients. For these reasons it may be necessary to cardiovert patients either electrically or chemically to sinus rhythm. Prior studies have shown a 5-7% incidence of embolization among patients who have not received anticoagulation prior to being cardioverted. Thus, current recommendations require prolonged periods of anticoagulation with cardioversion.16-21 The risk of embolization for cardioversion can be reduced to 1.6% with anticoagulation.17Jg Because anticoagulation carries its own intrinsic complications, investigations have examined the use of transesophageal echocardiography (TEE) to exclude thrombi when attempting to cardiovert without prolonged anticoagulation. Although there are no controlled randomized prospective trials, early data suggest that TEE can verify the absence of thrombi, but these data are very controversial and not uniform. Further prospective trials are needed to clarify this unsettled subject.
CLINICAL TRIALS There is a clear association between rheumatic valvular disease, atria1 fibrillation, and embolic stroke, thereby warranting the use of antithrombotic therapy. Although there is a 5-fold increased incidence of systemic emboli in nonrheumatic atria1 fibrillation, the use of anticoagulation or antiplatlet therapy remained controversial and was the impetus for the major clinical trials in nonrheumatic atria1 fibrillation. The results of 6 major clinical trials have clearly shown a reduction in the incidence of stroke with antithrombotic therapy, but with an associated risk of hemorrhagic complications. We will review those trials in detail and the conclusions reached by each. Copenhagen Anticoagulation
Atrial Fibrillation Aspirin and Study: The Copenhagen Atria1
Fibrillation Aspirin and Anticoagulation trial (AFASAK)22 was the first published randomized trial in nonrheumatic atria1 fibrillation using antithrombotic therapy (Table I). The study included 1007 patients (540 male, 467 female) with chronic nonrheumatic atria1 fibrillation. Patients were randomized to receive warfarin, aspirin, or placebo.
The warfarin was open labeled, and the aspirin (75 mg/day) and placebo were double-blinded. The primary endpoint was a thromboembolic event or major bleeding episode, with the secondary endpoint being death. There was a significant reduction of risk of reaching the primary endpointfrom 5.5% to 1.6% per year-on warfarin. However, there were 5 events in the warfarin group, including 1 intracerebral bleed. In addition, 38% of patients in the warfarin group discontinued therapy, compared with 13% and 15% in the aspirin and placebo groups respectively; 21 of the withdrawals in the warfarin group were secondary to nonfatal bleeds, compared with 2 in the aspirin group and none in the placebo group. Bleeding occurred in 6% of patients on warfarin, 1% on aspirin, and none in the placebo. Interestingly, of the 5 patients with strokes in the warfarin group, 1 occurred with adequate anticoagulation, 2 after treatment had been discontinued, and 1 on the day of randomization. There was no statistical decrease in the primary outcome events in the aspirin versus placebo groups by intention to treat. Approximately half of the patients in the placebo group took aspirin 75 mglday. There was no reduction in risk with aspirin at this dose. AFASAK showed a significant reduction of primary events with anticoagulation, with a minimal increase in hemorrrhagic complications. This benefit did not extend to aspirin, but this may have been because of the low dose of aspirin that was used. The principal weaknesses of the trial included unblinded warfarin therapy, a high incidence of congestive heart failure, and the inclusion of relatively old patients. Although this trial suggests a benefit for warfarin, it left unanswered questions, some of which were addressed in subsequent trials. Boston Area Anticoagulation Trial for Atrial Fibrillation: The Boston Area Anticoagulation Trial
for Atria1 Fibrillation (BAATAF)23 was an unblinded study of patients with paroxysmal or chronic nonvalvular atria1 fibrillation (Table II). A total of 420 patients were randomized to placebo versus warfarin and followed for an average of 2.2 years; 212 patients were randomized to warfarin, and 208 to placebo. The target international normalized ratio (INR) for those assigned to warfarin was 1.5-2.7. The placebo group was permitted to take aspirin, and 46% did. All data were analyzed by intention to treat, and the primary events were defined as ischemic stroke and systemic embolism. The study was stopped early because interim analysis of the data showed a very favorable effect of A SYMPOSIUM: ATRIAL FIBRILLATION
39A
warfarin. Specifically, there were 2 strokes in the patients assigned to warfarin, compared with 13 in the control group. This was consistent with an 86% reduction of risk for stroke. Patients with paroxysmal versus chronic atria1 fibrillation had similar risk for stroke. In addition, the duration of the atria1 fibrillation, left atria1 size, or presence of hypertension did not change the risk of stroke in this population. There were 2 major bleeding episodes in the warfarin group (1 intracerebral hemorrhage), and 1 in the control groups. The warfarin group also had 38 minor bleeding episodes compared to 21 in the control group. Thus, BAATAF also showed a benefit of warfarin in patients with nonrheumatic atria1 fibrillation. Although 46% of the placebo group used aspirin, it had no demonstrable benefit. In addition this trial showed no difference in risk of stroke for chronic or paroxysmal atria1 fibrillation.
fects of warfarin in this population with nonrheumatic atria1 fibrillation. This trial differed from the others in that it looked at primary and secondary prevention of stroke. The use of aspirin was not addressed. Stroke Prevention
in Atrial
Fibrillation
Study:
The first Stroke Prevention in Atria1 Fibrillation (SPAF I) tria125 randomized 1330 patients with chronic or intermittent nonvalvular atria1 fibrillation. Patients were stratified depending on their ability to take warfarin. The warfarin-eligible group was randomized to warfarin (INR 2-4.5), aspirin (325 mg), or placebo. The ineligible group received aspirin or placebo. There were 627 patients warfarin eligible, and 210 were randomized to warfarin; 703 were warfarin ineligible and were randomized (with the 417 remaining warfarin-eligible patients) to aspirin or placebo (Table IV). The primary outcome was ischemic stroke and Veterans Affairs Stroke Prevention in Atrial systemic embolization, analyzed by intention to Fibrillation Study: The Veterans Affairs Stroke treat. Secondary events were death, myocardial Prevention in Atria1 Fibrillation (SPINAF) tria124 infarction, transient ischemic attack, or unstable was a double-blind, placebo-controlled study with angina. Warfarin therapy was unblinded and aspipatients randomized to warfarin (INR 1.4-2.8) or rin therapy was double-blinded. placebo (Table III). A total of 571 participants The final publication reported the effects of with nonrheumatic atria1 fibrillation were random- warfarin, aspirin, and placebo separately. The ized and then stratified based on a previous history study found an overall reduction of primary events of stroke (525 without, 46 with). The mean fol- from 7.4% to 2.3% with warfarin, a 67% risk low-up was 1.7 years, and the primary endpoint was reduction. Interestingly, of the 7 events (6 strokes) cerebral infarction. Secondary endpoints were cerein patients assigned to warfarin, only 2 occurred bral hemorrhage and death. Data were analyzed by with adequate anticoagulation. In those patients intention to treat. randomized to aspirin and placebo there was a In the group of 525 patients without a previous 42% risk reduction with aspirin, from 6.3% to 3.6% stroke, there were 4 events in the 260 participants on warfarin and 19 in the 265 participants on per year. The trial was terminated early after a placebo. The study was terminated early because mean of 1.3 years of patient follow-up because of the first interim analysis showed a marked decrease significant decrease’in the number of events in the in cerebral infarctions in the warfarin group. The active treatment arm. Because there were few primary outcome in the placebo group was 4.3% outcome events in the warfarin-eligible group, it per year compared with 0.9% per year in the was impossible to differentiate aspirin from warfawarfarin group, or a reduction in relative risk of rin. Even if all 7 events were in either the aspirin or 79% (Table III). There were 228 patients >70 warfarin groups, treatment would still have been years old who had an annual event rate of 4.8% on better than placebo, with a risk reduction of 61%. The 627 patients in the warfarin-eligible group placebo, and 0.9% on warfarin. had a complication rate of 1.5%, 1.4%, and 1.6% As expected, cerebral infarctions were more per year for patients treated with warfarin, aspirin, common in the 46 patients with a history of and placebo, respectively. All the complications in cerebral infarction. However, there was a reduction in the rate of recurrent infarction, from 9.3% the warfarin-treated group were hemorrhagic. Interestingly, because of the low incidence of complito 6.1% per year. In the 281 patients on warfarin there was 1 cerebral hemorrhage in a 73-year-old cations in those patients receiving warfarin, there patient. There were 10 major gastrointestinal bleed- were more hemorrhagic complications in the plaing episodes, 4 on placebo (0.9% per year) and 6 on cebo group. In those patients randomized to aspirin, there was an absolute decrease in major warfarin (1.3% per year). bleeding episodes of 0.5% per year, and an inSPINAF also demonstrated the beneficial ef40A
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crease of 0.5% per year of bleeding with residua, compared with placebo. In a second analysis of the data comparing the 1120 aspirin- or placebo-treated patients, the event rates for aspirin and placebo were 3.6% and 6.3%, respectively which is a 42% risk reduction. Subgroup analysis showed that the difference was predominantly in patients <75 years old. Those patients >75 years had no risk reduction with aspirin over placebo (7.4% in both groups). This trial thus showed the benefit of antithrombotic therapy in nonrheumatic atria1 fibrillation. There were very few events in either the warfarin or aspirin arm, too few to distinguish between the 2 treatment modalities. This trial was then continued as SPAF II, which was designed to compare warfarin versus aspirin. Stroke Prevention
in Atrial
Fibrillation
Trial II:
The second Stroke Prevention in Atria1 Fibrillation (SPAF II) tria126 was a follow-up study that included patients assigned to warfarin or aspirin from the SPAF I trial; it was designed to compare those treatments according to patient age (Table V). The placebo group from SPAF I was rerandomized to aspirin or warfarin, together with newly recruited patients, for a total study group of 1100 patients. The trial included 715 patients < 75 years old (mean, 64), and 385 patients >75 years old (mean, 80) randomized to warfarin (INR 2-4.5) or aspirin (325 mg). All data were analyzed by intention to treat. The mean follow-up for the patients > 75 years old was 2.0 years, and for those < 75 years old was 3.1 years. At the termination of the study, treatment with warfarin was found to be superior to aspirin in all age groups. Due to the high rate of intracranial hemorrhage in the warfarin group (especially in those > 75 years old), most of the warfarin benefit was invalidated. In addition, patients without congestive heart failure, hypertension, or prior thromboembolism had a stroke rate of 0.5% per year on aspirin, sufficiently low so that the routine use of warfarin in this group was not believed to be warranted. Although this study demonstrated the benefit of warfarin and aspirin, it also showed the associated risk of this therapy. Warfarin was shown to be superior in all groups, and its major advantages wcrc in those with increased age and associated risk factors, which is also the group with the highest incidence of hemorrhagic complications. This study confirmed that enthusiasm for warfarin must be tempered by consideration of its hcmorrhagic complications.
TABLE
I Copenhagen
Anticoogulation
Atrial
Study
Fibrillatron
Aspirin
and
(AFASAK)
No. potlent
iO07
75
Age (yr; meon) Sample size WGrfOGn
335 336 336 2.8 4 2
Aspirin Placebo INR Control
group
Aspirrn
Placebo
1’ or 2” prevention Worforrn
1”
b!inded
1” 0LIcome
NO
ever1
S, E, T. H Eff’COCY
An0lpis Meon
vs ospmn
75
(mg)
follow-up
(yr)
12
Relotrve nsk reductron WoffOrIn
(%) 71
18
Aspirrn
TABLE
II
Boston
Area
Anticoagulation
Trio1 for Atria1
Fibrillation
( BAATAF) No.
420 68
potrent
Age jyr; mean) Sample
srze
212 208 1.S2.7
Warfarin Placebo INR Control
group
Usual
1’ or 2” prevention Wodorin
blrnded
1’ Outcome
NO
event
5, E In-T
Analysis lMeo!l follow-up (y-) Relative risk reduct’on
2.2 of s:roke
(%)
86
WOrfOrln ITT. ~n%n+,o~ 10 !reot. for other abbrwtilons,
TABLE Ill Study
Veterans
Affairs
Stroke
see -ab e I
Prevention
in Atrial
Fibrillation
(SPINAF)
No. patients
rondomrzed
571
67
Age (yr; rncon) Somole
size
281 290 1.4-2.8
Wor’orin Placebo INR Control
Placebo
group
I5 T 2'
1’ or 2” prevention Worforin
blinded
I” oulcome
Yes
event
5, H ITT
Anolysrs Mean Relotrve
core I0
follow-up
18
(yr)
nsk reductron
(“‘%) (1’ endpornt)
79
Wodor1n cor abbrevlax,nr,
see Tables I a-d
!.
Canadian Atrial Fibrillcltion Anticoagulation Study: The Canadian Atria1 Fibrillation Anticoagu-
lation (CAFA) study2’ enrolled 383 patients with chronic or intermittent atria1 fibrillation and randomized them in a double-blinded fashion to warfarin (INR 2-3) or placebo (Table VI). The A SYMPOSIUM:
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r
TABLE VI
Canadian
Atriol
Fibrillation
Anticoogulotlon
Trial
(CAFA)
No
383 67
patients
Age (yr; mean] SolIDle
Size
Woiarin
187
Aspirin 191
?locebc
2.0-3.0
INR Ccnlrcl
1’ 0’ 2” prevention Worfor~n
1” cLJ:come
Placebo
~‘cup
Warfur~n
event
Stroke
Prevention
in Atrial
Fibrillation
Trial
II (SPAf
64 80 SIZI?
Asplnr, INR
Ccnrrcl group
Woriortn
jmg)
IF 0~2’pre”entlon
Group
(EAFTA)
1
71
77
we
225 404 378 2 5-40
Placebo
vs uspirfn
INR
325 I’
Aspirin
;o
Warfcr~n
Ccntrcl
group
Placebo
risk reduction
WvsA
<75yr
Wvs
A > 75 yr
bl’nded
NC
even’
S, E, H, V. M !T
AnOlySls
3.1 2
Mean
iollow-Lp
Relotlve
(‘3’3)
Wahn 105
Aspirer
2.3
(yr)
risk reduction
(%)
Group
’ (W & P)
Groups
I Fr, 2 (A 8 P)
9
W, worlor P, A, asp -I”, ks oher abbwamnr,
vs csp~r~n
300 2’
(mg)
1 a outcome
(yr)
<75 >75 R&he
Study
2
Aspirer
I-T
:ollcw-up
lrial
Group
1 a or 7” preventIon
eveni
Ano ys~s Meon
Fibrillation
1007
W04Clr1n
blInded
I’ outcome
Atrial
Group
Sample
555 545 20-4 5
WCrfCrln
Worfor~n
European
Age (yr; mean)
<75 > 75
Asolrin
s, E, H, F
No. potlents
1100
No. pot,cn.s
Yes
ewrl
TABLE VII
II)
Age (yr, mean)
Sorrple
1’
blhnded
lo 02+cc:-e
TABLE V
vs wcrfor~-
lo or 2” preventlcn
blInded
69 16
see Tables’ ant II
Major bleeding occurred in 2.5% per year in the principal outcome was an aggregate of nonlacunar stroke, cerebral hemorrhage, systemic cmboliza- warfarin, and 0.5% per year in the placebo groups; although there were fewer primary events and tion, and fatal hemorrhage, using an “efficiency analysis,” whereby events occurring > 28 days after more bleeding episodes in patients on warfarin, the formal notification of discontinuation of study difference did not reach statistical significance medication would be excluded. If medication was because when the results of AFASAK and SPAF temporarily discontinued, those events that oc- were made public, the study was stopped premacurred during that period would be included in the turcly. Nevertheless, data from this study seem to analysis of efficacy. If a temporary discontinuation have supported the theory that warfarin is a useful became permanent, the time of formal notification therapy to prevent stroke in patients with atria1 would start the 28-day waiting period. Patient fibrillation. European Atrial Fibrillation Trial: In the Eurodiscontinuation was 26% for warfarin and 23% for placebo. The mean follow-up was 15.2 months. The pean Atria1 Fibrillation Trial (EAFT),*s 1007 parate of ischemic stroke in the warfarin group was tients with nonrheumatic atria1 fibrillation and a 3.5% per year versus 5.2% per year in the placebo, history of a recent stroke or transient ischemic a 37% risk reduction. For patients treated with attack were randomized to warfarin (INR 2.5-4), warfarin, the INR was therapeutic 43.7% of the aspirin (300 mg), or placebo (Table VII). The time. warfarin group was admitted open label, and aspi42A
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FIGURE 1. Antithrombotic Koonlawee Nademanee,
therapy with warfarin unpublished.)
(Coumadin)
for patients with nonvalvular
rin and placebo were prescribed double-blind. Patients were grouped based on contraindications to anticoagulation. Group I (without contraindications) included 669 patients randomized to warfarin, aspirin, or placebo. Group II (with contraindications) included 338 patients randomized to aspirin or placebo. The combined endpoints were death from vascular disease, stroke, myocardial infarction, or systemic embolization, and follow-up was 2.3 years. Risk of reaching the combined endpoint was reduced by warfarin from 17% to 8% for group I patients. The risk of stroke in this group was reduced from 12% to 4% per year. Among patients assigned to aspirin in both groups, the annual rate of outcome events was reduced from 19% to 15%. The incidence of bleeding was low in both groups, 2.8% per year in the anticoagulation group and 0.9% per year in the aspirin. There was no intracranial bleeding in those patients assignedto warfarin. COMBINED ANALYSIS A meta-analysis of the 5 original atria1 fibrillation stroke-prevention trials (not including EAFTA) combined the data from all of the trials.” The database identified 4 independent clinical features by multivariate analysis that identified patients with atria1 fibrillation at an increased risk for stroke. These included a previous transient ischemic attack, diabetes mellitus, hypertension, and increasing age. Patients with any risk factor, if left untreated, had a 4% annual risk of stroke. Patients with cardiac disorders such as congestive heart failure and coronary artery disease had a stroke rate 3 times higher than patients without any risk factors. Patients with lone atria1 fibrillation <60 years old had no strokes. In patients 60-69 years old, there was a 1.6% incidence of stroke, compared with a 2.1% incidence of stroke in patients 70-79 years old. Finally, 25% of patients in the trials were women, in whom warfarin and aspirin decreased the risk of stroke by 84% and 23%, respectively.
atrial fibrillation.
(Adapted
from
CONCLUSION Nonrheumatic atria1 fibrillation, especially in the elderly, is a common cause of stroke. There have now been 6 major randomized clinical trials that have supported the use of anticoagulation in this population. A meta-analysis of the data from these trials has shown a 64% risk reduction for stroke in patients treated with warfarin compared with placebo. Atria1 fibrillation without concomitant risk factors or structural heart diseaseseem to confer little risk for stroke. The value of warfarin in patients > 75 years remains unclear because of a high risk of hemorrhagic complication. The use of the INR to guide warfarin therapy may help lower the rate of bleeding complications.2g Although these studies indicate the value of warfarin or aspirin for specific groups of patients we believe that therapy must be individualized; the data from these trials can only be used as a guide in management of this complex patient population. Figure 1 is a flow diagram that offers a suggestion as to how specific patient groups might be managed based on age and risk categories. The highest risk cohorts clearly benefit from warfarin. Those at lower risk need no therapy. Many future clinical trials will focus on those at intermediate risk to determine the best antithrombotic regimen and how to administer it for maximum efficacy and at minimal risk. Acknowledgment: We thank Roe Wells and Sheila Canovan for their assistancein the preparation of the manuscript. 1. Abbott W, Maloney RD, McCabe CC, Lee CE, Witthlin LS. Arterial embolism:a 44 year perspective./lm J Swg 1982;143:46OX4. 2. Kannel W, Abbott R, SavageD, McNamara P. Epidemiologic features of chronic atrial fibrillation: the Framingham Study. N Engl J Med 1982;317: 101&1022. 3. Cairns JA, Connolly SJ: Nonrheumatic atrial fibrillation: Risk of stroke and role of antithrombotic therapy. Circulation 1991;84:469-481. 4. Pritchett ELC. Management of atria1 fibrillation. N [email protected] A4ed1992;326: 1264-1271. 5. The National Heart, Lung, and Blood Institute Working Group on Atria1 Fibrillation. Atria1 fibrillation: current understandings and research imperatives,.I Am Co11Cardiol 1993,22:1930-1934. 6. Repique LJ, Shah SN, Marais GE. Atria1 fibrillation-1992 management strategiesin flux. Chesf1992;101:1095-1103, 7. Ezekowitz MD. Personalcommunication.
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20. Petersen P, Godtfredsen J. Embolic complications in paroxysmal atrial fibrillation. Stroke1986;17:622&?6. 21. Rokseth R, Storstein 0. Quinidiie therapy of chronic auricular fibrillation. Med 1992$16:1-5. 9.Kopec$ SL, Gersh BJ, McGcxxr MD, Whimant JP, Ilstrup DM. Lone Arch In&m Med 1963;111:18&189. 22. Petersen P, Boysen G, Godtfredsen J, Andersen CD, Andersen B, et al. atrial fibriiiation in the elderly. A population-based long term study. (Abstr.) PlacebocontroUed, randomized trial of warfarhi and aspirin for prevention of Circulation 1989;8O(suppl II):409. 10. Atwood J, AIbers G. Anticoagulation and atria1 fibrillation. Hm 1993;18: thromboembolic complication in chronic atria1 fibriiiation: the Copenhagen AFASAK study.Lancet 1989;1:175-178. 27-38. 23. The Boston Area Anticoagtdation Trial for Atria1 Fibrillation Investigators: 11. Atria1 Fibrillation Investigators. Risk factors for stroke and efficacy of The effect of low dose warfarin on the risk of stroke in patients with nonantithrombotic therapy in atriai fibrillation: analysis of pooled data from five rheumatic atrial fibrillation. N Engl JMed 199@3U:1505-1511 randomizedtrials. Arch Intent Med 1994;154:1449-1457. 24. Ezekowitz MD, Bridgers SL, JamesKE, Carlier Mt Coliiig CL, Gomick 12. Takahashi N, Seki A, Imataka K, Fujii J. Chnicai features of paroxysmal CC, Krause-Steinrauf H, Kurtzke JF, Nazarian SM, Radford MJ, Rickles FR, atriaI fibrillation: an observation of 94 patients.Jpn Heart J 1981;22:143-149. ShabetaiR, Deykin D, for the Veterans Affairs Stroke Prevention in Nonrheu13. Petersen P, Godtfredsen J. EmboIic complications in paroxysmal atria1 matic Atriai Fibrillation Investigators.The Veterans AtIairs Stroke Prevention fibrillation. Srroke1986;17:6%6’26. in Nonrheumatic Atria1 Fibrillation investigators:warfarin in the prevention of 14. Petersen P, Pedersen F, Johnson A, Madsen EB, Brun B, Boysen G, stroke associatedwith nonrheumatic atriai fibrillation. N Engl J Med 1992;327: Godtfredsen J. Cerebral computer tomographyon paroxysmalatria1SbriIlation. 1406-1412. 25.The Stroke Prevention in Atrial Fibrillation Study Group Investigators. Acta Neural Scand 1989;79:482-486. Stroke prevention in atria1 fibrillation study: final results. Circ&ion 1991;84: 15. Morris JJ Jr, Entman M, North WC, Kong Y, McIntosh H. The changesin cardiac output with reversion of atriai fibrillation to sinus rhythm. Cim*lation 527-539. 26. Stroke Prevention in Atria1 Fibrillation Investigators. Warf’arin vems aspi1%5;31:67CUi78. 16. Resnekov L, McDonald L, complications in 220 patients with cardiac rin for prevention of thromboembolismin atrial fibrillation: Stroke Prevention in Atria1 Fibrillation II Study.Lancet 1994;343:687-691. dysrhythmiastreated by phaseddiiect current shock,and indications for electro27. Connohy SJ, Laupacis A Gent M, Roberts RS, Cairns JA, Joyner C, for conversion.Br Heart J 196729926-936. the CAFA Study coinvestigators.Canadian Atria1 Fibrillation A&coagulation 17. Bjerkelund CT, Oming OM. The efficacy of autocoagulation therapy in (CAFA) study.JAm Co11Cardiol1991;18:349-355. preventing embolism related to DC. electricaI conversion of atriai fibrillation. 28. European Atria1 Fibrillation Trial Study Group. SecondaIy prevention in Am J G&o1 1969;23:208-216 non-rheumatic atriai fibrillation after ischaetnicattack or manor stroke. Lancet 18. Lown B, Perloth MG, Kaidbey S, Abe T, Harken DE. “Cardioversion” of 1993;342:1255-1262. atria1 fibrillation: a report on the treatment of 65 episodes in 50 patients. N 29.Andrews TC, Peterson DW, Doeppenschmidt D, Foster JS, Lucca MJ, Engl J Med 1%%269:325-331. Deering JA, LaVeau PJ. Complications of warfarin therapy monitored by the 19. Weinberg DM, Mancini GBJ. Anticoagulation for, cardioversion of atria1 International Normaliid Ratio versus prothrombii time ratio. Clin Cardiol fibrillation. Am J Cardiol1989;63:745-746. 1995;18:80-82. 8. Stroke Prevention in AtriaI Fibrillation Investigators.Predictors of thromboembolismin atria1fibrillation: I. Clinical features of patients at risk. Ann Intern
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JANUARY ‘25, 1996
Fibrillation, Anticoagulation, and Stroke MD, Roger Marinchak,
MD, Seth J. Rials, MD, PhD, and Peter Kowey,
There is a demonstrated statistical association between atrial fibrillcrtion, rheumatic valvular disease, and embolic stroke. This article assesses the results of 6 major clinical trials (AFASAK, BAATAF, SPINAF, SPAF [parts I and II], CAFA and EAFTA-see text for trial names). Multivariate analysis revealed 4 independent clinical features that identified patients with atrial fibrillation at an increased risk for stroke: hypertension, increasing age, previous transient ischemic attack, and diabetes mellitus. Without anticoagulation therapy, patients with any of these risk factors had a 4% annual risk of stroke. Patients with
MD
cardiac disorders such as congestive heart failure and coronary artery disease have a stroke rate 3 times higher than patients without any risk factors; patients with atrial fibrillation but no concomitant risk factors or structuml heart disease seemed to have little concomitant risk for stroke. Meta-analysis revealed a 64% reduction of risk for stroke in patients treated with warfarin, as compared with placebo. The value of war-fat-in thempy in patients >75 years old is less clear because of a high risk of hemorrhagic complications. (Am J Cardioll996; 77:3BAaA)
A
trial fibrillation is one of the most common agonist, pericarditis, pulmonary embolism, and the arrhythmias seen in clinical practice, and is use of cholinergic drugs.jJj the primary cardiovascular disorder predisEmbolic stroke, a frequent consequence of atria1 posing patients to systemic embolization.’ Accord- fibrillation, results in death or severe neurologic ing to the Framingham Heart Study,’ atria1 fibrilladeficit in 50-70% of episodes.’ In addition to its tion has a prevalence of 4% in the adult population, devastating morbidity and mortality, the cost of which translates into > 1 million cases in the treating patients with cmbolic stroke in the United United States each year. The incidence of atria1 States in 1993 reached $18 billion.7 Although fibrillation increases with age; it is seen in < 1% of various studies have demonstrated a 5-fold inthe 40-65year-old group, in 2-5% of the M-74creased risk of stroke in nonrheumatic atria1 librilyear-old group, and > 5% of patients > 75 years.” lation, risk is highly dependent on the concomitant Approximately 50% of patients with atria1 tibrillacardiac disease. In the Framingham Heart Study, tion in the United States are >75 years old. The patients with lone atria1 fibrillation <60 years old most common cause of atrial fibrillation is hypertenhad no increased risk of cmbolic stroke. Yet, sion, but because of the high prevalence of hypernonrheumatic atria1 fibrillation in patients with tension in the general population it is not a statistically differentiating risk factor. In contrast, hypertension, recent congestive failure, or previous congestive heart failure and rheumatic heart dis- thromboembolism was associated with an inease, although less prevalent, have a stronger creased risk for stroke of > 7% per year.8,9Atria1 association with risk of atria1 fibrillation.4 The fibrillation is responsible for 7-310/o of all strokes in Framingham Heart Study identified left atrial en- patients > 60 years old.2 In addition, patients with largement, increased left ventricular wall thick- chronic atria1 fibrillation but no apparent evidence ness, and decreased left ventricular shortening of embolic stroke have a high incidence of abnorfraction as independent risk factors for atria1 mal computed tomography scans, suggesting silent fibrillation. Extracardiac risk factors associated cerebral infarctions.lO The incidence of stroke in paroxysmal atrial with atria1 fibrillation include hypertension, diabetes mellitus, systemic illness, pneumonia, chronic fibrillation has been clarified by a combined analyobstructive lung disease, electrolyte disturbance, sis of data from the 5 mcgatrials on atria1 fibrillaalcohol intoxication, use of theophylline or beta tion, stroke, and anticoagulation.” This analysis indicates that paroxysmal and chronic atria1 fibrillation have a similar risk for embolic stroke, regardFrom the Division of Cardiovascular Diseases, The Lankenau Hospital less of the time spent in atria1 fibrillation. This and Medical Research Center, Wynnewood, Pennsylvania, and The contradicts data from Framingham, which showed Jefferson Medical College of Thomos Jefferson University, Philadelphia, Pennsylvania. men with chronic atria1 fibrillation had an annual Address for reprints: Peter R. Kowey, MD, The Lonkenau Hospital, stroke rate of 5.4%, whereas for paroxysmal atria1 Medical Office Building East, Suite 556, 100 Lancaster Avenue, fibrillation it was only 1.3%. In fact, 3 other studies Wynnewood, Pennsylvania 19096. 38A
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have reported an even lower incidence of stroke in paroxysmal atria1 fibrillation.r2-l4 Atria1 fibrillation is an arrhythmia characterized by an electrical and mechanical abnormality that predisposes to blood stasis and subsequent thrombi formation in the atria. Under certain circumstances, atria1 fibrillation can lead to hemodynamic compromise secondary to loss of atria1 kick.lS In addition, atria1 fibrillation causes an increase in symptomatic distress in many patients. For these reasons it may be necessary to cardiovert patients either electrically or chemically to sinus rhythm. Prior studies have shown a 5-7% incidence of embolization among patients who have not received anticoagulation prior to being cardioverted. Thus, current recommendations require prolonged periods of anticoagulation with cardioversion.16-21 The risk of embolization for cardioversion can be reduced to 1.6% with anticoagulation.17Jg Because anticoagulation carries its own intrinsic complications, investigations have examined the use of transesophageal echocardiography (TEE) to exclude thrombi when attempting to cardiovert without prolonged anticoagulation. Although there are no controlled randomized prospective trials, early data suggest that TEE can verify the absence of thrombi, but these data are very controversial and not uniform. Further prospective trials are needed to clarify this unsettled subject.
CLINICAL TRIALS There is a clear association between rheumatic valvular disease, atria1 fibrillation, and embolic stroke, thereby warranting the use of antithrombotic therapy. Although there is a 5-fold increased incidence of systemic emboli in nonrheumatic atria1 fibrillation, the use of anticoagulation or antiplatlet therapy remained controversial and was the impetus for the major clinical trials in nonrheumatic atria1 fibrillation. The results of 6 major clinical trials have clearly shown a reduction in the incidence of stroke with antithrombotic therapy, but with an associated risk of hemorrhagic complications. We will review those trials in detail and the conclusions reached by each. Copenhagen Anticoagulation
Atrial Fibrillation Aspirin and Study: The Copenhagen Atria1
Fibrillation Aspirin and Anticoagulation trial (AFASAK)22 was the first published randomized trial in nonrheumatic atria1 fibrillation using antithrombotic therapy (Table I). The study included 1007 patients (540 male, 467 female) with chronic nonrheumatic atria1 fibrillation. Patients were randomized to receive warfarin, aspirin, or placebo.
The warfarin was open labeled, and the aspirin (75 mg/day) and placebo were double-blinded. The primary endpoint was a thromboembolic event or major bleeding episode, with the secondary endpoint being death. There was a significant reduction of risk of reaching the primary endpointfrom 5.5% to 1.6% per year-on warfarin. However, there were 5 events in the warfarin group, including 1 intracerebral bleed. In addition, 38% of patients in the warfarin group discontinued therapy, compared with 13% and 15% in the aspirin and placebo groups respectively; 21 of the withdrawals in the warfarin group were secondary to nonfatal bleeds, compared with 2 in the aspirin group and none in the placebo group. Bleeding occurred in 6% of patients on warfarin, 1% on aspirin, and none in the placebo. Interestingly, of the 5 patients with strokes in the warfarin group, 1 occurred with adequate anticoagulation, 2 after treatment had been discontinued, and 1 on the day of randomization. There was no statistical decrease in the primary outcome events in the aspirin versus placebo groups by intention to treat. Approximately half of the patients in the placebo group took aspirin 75 mglday. There was no reduction in risk with aspirin at this dose. AFASAK showed a significant reduction of primary events with anticoagulation, with a minimal increase in hemorrrhagic complications. This benefit did not extend to aspirin, but this may have been because of the low dose of aspirin that was used. The principal weaknesses of the trial included unblinded warfarin therapy, a high incidence of congestive heart failure, and the inclusion of relatively old patients. Although this trial suggests a benefit for warfarin, it left unanswered questions, some of which were addressed in subsequent trials. Boston Area Anticoagulation Trial for Atrial Fibrillation: The Boston Area Anticoagulation Trial
for Atria1 Fibrillation (BAATAF)23 was an unblinded study of patients with paroxysmal or chronic nonvalvular atria1 fibrillation (Table II). A total of 420 patients were randomized to placebo versus warfarin and followed for an average of 2.2 years; 212 patients were randomized to warfarin, and 208 to placebo. The target international normalized ratio (INR) for those assigned to warfarin was 1.5-2.7. The placebo group was permitted to take aspirin, and 46% did. All data were analyzed by intention to treat, and the primary events were defined as ischemic stroke and systemic embolism. The study was stopped early because interim analysis of the data showed a very favorable effect of A SYMPOSIUM: ATRIAL FIBRILLATION
39A
warfarin. Specifically, there were 2 strokes in the patients assigned to warfarin, compared with 13 in the control group. This was consistent with an 86% reduction of risk for stroke. Patients with paroxysmal versus chronic atria1 fibrillation had similar risk for stroke. In addition, the duration of the atria1 fibrillation, left atria1 size, or presence of hypertension did not change the risk of stroke in this population. There were 2 major bleeding episodes in the warfarin group (1 intracerebral hemorrhage), and 1 in the control groups. The warfarin group also had 38 minor bleeding episodes compared to 21 in the control group. Thus, BAATAF also showed a benefit of warfarin in patients with nonrheumatic atria1 fibrillation. Although 46% of the placebo group used aspirin, it had no demonstrable benefit. In addition this trial showed no difference in risk of stroke for chronic or paroxysmal atria1 fibrillation.
fects of warfarin in this population with nonrheumatic atria1 fibrillation. This trial differed from the others in that it looked at primary and secondary prevention of stroke. The use of aspirin was not addressed. Stroke Prevention
in Atrial
Fibrillation
Study:
The first Stroke Prevention in Atria1 Fibrillation (SPAF I) tria125 randomized 1330 patients with chronic or intermittent nonvalvular atria1 fibrillation. Patients were stratified depending on their ability to take warfarin. The warfarin-eligible group was randomized to warfarin (INR 2-4.5), aspirin (325 mg), or placebo. The ineligible group received aspirin or placebo. There were 627 patients warfarin eligible, and 210 were randomized to warfarin; 703 were warfarin ineligible and were randomized (with the 417 remaining warfarin-eligible patients) to aspirin or placebo (Table IV). The primary outcome was ischemic stroke and Veterans Affairs Stroke Prevention in Atrial systemic embolization, analyzed by intention to Fibrillation Study: The Veterans Affairs Stroke treat. Secondary events were death, myocardial Prevention in Atria1 Fibrillation (SPINAF) tria124 infarction, transient ischemic attack, or unstable was a double-blind, placebo-controlled study with angina. Warfarin therapy was unblinded and aspipatients randomized to warfarin (INR 1.4-2.8) or rin therapy was double-blinded. placebo (Table III). A total of 571 participants The final publication reported the effects of with nonrheumatic atria1 fibrillation were random- warfarin, aspirin, and placebo separately. The ized and then stratified based on a previous history study found an overall reduction of primary events of stroke (525 without, 46 with). The mean fol- from 7.4% to 2.3% with warfarin, a 67% risk low-up was 1.7 years, and the primary endpoint was reduction. Interestingly, of the 7 events (6 strokes) cerebral infarction. Secondary endpoints were cerein patients assigned to warfarin, only 2 occurred bral hemorrhage and death. Data were analyzed by with adequate anticoagulation. In those patients intention to treat. randomized to aspirin and placebo there was a In the group of 525 patients without a previous 42% risk reduction with aspirin, from 6.3% to 3.6% stroke, there were 4 events in the 260 participants on warfarin and 19 in the 265 participants on per year. The trial was terminated early after a placebo. The study was terminated early because mean of 1.3 years of patient follow-up because of the first interim analysis showed a marked decrease significant decrease’in the number of events in the in cerebral infarctions in the warfarin group. The active treatment arm. Because there were few primary outcome in the placebo group was 4.3% outcome events in the warfarin-eligible group, it per year compared with 0.9% per year in the was impossible to differentiate aspirin from warfawarfarin group, or a reduction in relative risk of rin. Even if all 7 events were in either the aspirin or 79% (Table III). There were 228 patients >70 warfarin groups, treatment would still have been years old who had an annual event rate of 4.8% on better than placebo, with a risk reduction of 61%. The 627 patients in the warfarin-eligible group placebo, and 0.9% on warfarin. had a complication rate of 1.5%, 1.4%, and 1.6% As expected, cerebral infarctions were more per year for patients treated with warfarin, aspirin, common in the 46 patients with a history of and placebo, respectively. All the complications in cerebral infarction. However, there was a reduction in the rate of recurrent infarction, from 9.3% the warfarin-treated group were hemorrhagic. Interestingly, because of the low incidence of complito 6.1% per year. In the 281 patients on warfarin there was 1 cerebral hemorrhage in a 73-year-old cations in those patients receiving warfarin, there patient. There were 10 major gastrointestinal bleed- were more hemorrhagic complications in the plaing episodes, 4 on placebo (0.9% per year) and 6 on cebo group. In those patients randomized to aspirin, there was an absolute decrease in major warfarin (1.3% per year). bleeding episodes of 0.5% per year, and an inSPINAF also demonstrated the beneficial ef40A
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crease of 0.5% per year of bleeding with residua, compared with placebo. In a second analysis of the data comparing the 1120 aspirin- or placebo-treated patients, the event rates for aspirin and placebo were 3.6% and 6.3%, respectively which is a 42% risk reduction. Subgroup analysis showed that the difference was predominantly in patients <75 years old. Those patients >75 years had no risk reduction with aspirin over placebo (7.4% in both groups). This trial thus showed the benefit of antithrombotic therapy in nonrheumatic atria1 fibrillation. There were very few events in either the warfarin or aspirin arm, too few to distinguish between the 2 treatment modalities. This trial was then continued as SPAF II, which was designed to compare warfarin versus aspirin. Stroke Prevention
in Atrial
Fibrillation
Trial II:
The second Stroke Prevention in Atria1 Fibrillation (SPAF II) tria126 was a follow-up study that included patients assigned to warfarin or aspirin from the SPAF I trial; it was designed to compare those treatments according to patient age (Table V). The placebo group from SPAF I was rerandomized to aspirin or warfarin, together with newly recruited patients, for a total study group of 1100 patients. The trial included 715 patients < 75 years old (mean, 64), and 385 patients >75 years old (mean, 80) randomized to warfarin (INR 2-4.5) or aspirin (325 mg). All data were analyzed by intention to treat. The mean follow-up for the patients > 75 years old was 2.0 years, and for those < 75 years old was 3.1 years. At the termination of the study, treatment with warfarin was found to be superior to aspirin in all age groups. Due to the high rate of intracranial hemorrhage in the warfarin group (especially in those > 75 years old), most of the warfarin benefit was invalidated. In addition, patients without congestive heart failure, hypertension, or prior thromboembolism had a stroke rate of 0.5% per year on aspirin, sufficiently low so that the routine use of warfarin in this group was not believed to be warranted. Although this study demonstrated the benefit of warfarin and aspirin, it also showed the associated risk of this therapy. Warfarin was shown to be superior in all groups, and its major advantages wcrc in those with increased age and associated risk factors, which is also the group with the highest incidence of hemorrhagic complications. This study confirmed that enthusiasm for warfarin must be tempered by consideration of its hcmorrhagic complications.
TABLE
I Copenhagen
Anticoogulation
Atrial
Study
Fibrillatron
Aspirin
and
(AFASAK)
No. potlent
iO07
75
Age (yr; meon) Sample size WGrfOGn
335 336 336 2.8 4 2
Aspirin Placebo INR Control
group
Aspirrn
Placebo
1’ or 2” prevention Worforrn
1”
b!inded
1” 0LIcome
NO
ever1
S, E, T. H Eff’COCY
An0lpis Meon
vs ospmn
75
(mg)
follow-up
(yr)
12
Relotrve nsk reductron WoffOrIn
(%) 71
18
Aspirrn
TABLE
II
Boston
Area
Anticoagulation
Trio1 for Atria1
Fibrillation
( BAATAF) No.
420 68
potrent
Age jyr; mean) Sample
srze
212 208 1.S2.7
Warfarin Placebo INR Control
group
Usual
1’ or 2” prevention Wodorin
blrnded
1’ Outcome
NO
event
5, E In-T
Analysis lMeo!l follow-up (y-) Relative risk reduct’on
2.2 of s:roke
(%)
86
WOrfOrln ITT. ~n%n+,o~ 10 !reot. for other abbrwtilons,
TABLE Ill Study
Veterans
Affairs
Stroke
see -ab e I
Prevention
in Atrial
Fibrillation
(SPINAF)
No. patients
rondomrzed
571
67
Age (yr; rncon) Somole
size
281 290 1.4-2.8
Wor’orin Placebo INR Control
Placebo
group
I5 T 2'
1’ or 2” prevention Worforin
blinded
I” oulcome
Yes
event
5, H ITT
Anolysrs Mean Relotrve
core I0
follow-up
18
(yr)
nsk reductron
(“‘%) (1’ endpornt)
79
Wodor1n cor abbrevlax,nr,
see Tables I a-d
!.
Canadian Atrial Fibrillcltion Anticoagulation Study: The Canadian Atria1 Fibrillation Anticoagu-
lation (CAFA) study2’ enrolled 383 patients with chronic or intermittent atria1 fibrillation and randomized them in a double-blinded fashion to warfarin (INR 2-3) or placebo (Table VI). The A SYMPOSIUM:
ATRIAL
FIBRILIATION
41A
r
TABLE VI
Canadian
Atriol
Fibrillation
Anticoogulotlon
Trial
(CAFA)
No
383 67
patients
Age (yr; mean] SolIDle
Size
Woiarin
187
Aspirin 191
?locebc
2.0-3.0
INR Ccnlrcl
1’ 0’ 2” prevention Worfor~n
1” cLJ:come
Placebo
~‘cup
Warfur~n
event
Stroke
Prevention
in Atrial
Fibrillation
Trial
II (SPAf
64 80 SIZI?
Asplnr, INR
Ccnrrcl group
Woriortn
jmg)
IF 0~2’pre”entlon
Group
(EAFTA)
1
71
77
we
225 404 378 2 5-40
Placebo
vs uspirfn
INR
325 I’
Aspirin
;o
Warfcr~n
Ccntrcl
group
Placebo
risk reduction
WvsA
<75yr
Wvs
A > 75 yr
bl’nded
NC
even’
S, E, H, V. M !T
AnOlySls
3.1 2
Mean
iollow-Lp
Relotlve
(‘3’3)
Wahn 105
Aspirer
2.3
(yr)
risk reduction
(%)
Group
’ (W & P)
Groups
I Fr, 2 (A 8 P)
9
W, worlor P, A, asp -I”, ks oher abbwamnr,
vs csp~r~n
300 2’
(mg)
1 a outcome
(yr)
<75 >75 R&he
Study
2
Aspirer
I-T
:ollcw-up
lrial
Group
1 a or 7” preventIon
eveni
Ano ys~s Meon
Fibrillation
1007
W04Clr1n
blInded
I’ outcome
Atrial
Group
Sample
555 545 20-4 5
WCrfCrln
Worfor~n
European
Age (yr; mean)
<75 > 75
Asolrin
s, E, H, F
No. potlents
1100
No. pot,cn.s
Yes
ewrl
TABLE VII
II)
Age (yr, mean)
Sorrple
1’
blhnded
lo 02+cc:-e
TABLE V
vs wcrfor~-
lo or 2” preventlcn
blInded
69 16
see Tables’ ant II
Major bleeding occurred in 2.5% per year in the principal outcome was an aggregate of nonlacunar stroke, cerebral hemorrhage, systemic cmboliza- warfarin, and 0.5% per year in the placebo groups; although there were fewer primary events and tion, and fatal hemorrhage, using an “efficiency analysis,” whereby events occurring > 28 days after more bleeding episodes in patients on warfarin, the formal notification of discontinuation of study difference did not reach statistical significance medication would be excluded. If medication was because when the results of AFASAK and SPAF temporarily discontinued, those events that oc- were made public, the study was stopped premacurred during that period would be included in the turcly. Nevertheless, data from this study seem to analysis of efficacy. If a temporary discontinuation have supported the theory that warfarin is a useful became permanent, the time of formal notification therapy to prevent stroke in patients with atria1 would start the 28-day waiting period. Patient fibrillation. European Atrial Fibrillation Trial: In the Eurodiscontinuation was 26% for warfarin and 23% for placebo. The mean follow-up was 15.2 months. The pean Atria1 Fibrillation Trial (EAFT),*s 1007 parate of ischemic stroke in the warfarin group was tients with nonrheumatic atria1 fibrillation and a 3.5% per year versus 5.2% per year in the placebo, history of a recent stroke or transient ischemic a 37% risk reduction. For patients treated with attack were randomized to warfarin (INR 2.5-4), warfarin, the INR was therapeutic 43.7% of the aspirin (300 mg), or placebo (Table VII). The time. warfarin group was admitted open label, and aspi42A
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FIGURE 1. Antithrombotic Koonlawee Nademanee,
therapy with warfarin unpublished.)
(Coumadin)
for patients with nonvalvular
rin and placebo were prescribed double-blind. Patients were grouped based on contraindications to anticoagulation. Group I (without contraindications) included 669 patients randomized to warfarin, aspirin, or placebo. Group II (with contraindications) included 338 patients randomized to aspirin or placebo. The combined endpoints were death from vascular disease, stroke, myocardial infarction, or systemic embolization, and follow-up was 2.3 years. Risk of reaching the combined endpoint was reduced by warfarin from 17% to 8% for group I patients. The risk of stroke in this group was reduced from 12% to 4% per year. Among patients assigned to aspirin in both groups, the annual rate of outcome events was reduced from 19% to 15%. The incidence of bleeding was low in both groups, 2.8% per year in the anticoagulation group and 0.9% per year in the aspirin. There was no intracranial bleeding in those patients assignedto warfarin. COMBINED ANALYSIS A meta-analysis of the 5 original atria1 fibrillation stroke-prevention trials (not including EAFTA) combined the data from all of the trials.” The database identified 4 independent clinical features by multivariate analysis that identified patients with atria1 fibrillation at an increased risk for stroke. These included a previous transient ischemic attack, diabetes mellitus, hypertension, and increasing age. Patients with any risk factor, if left untreated, had a 4% annual risk of stroke. Patients with cardiac disorders such as congestive heart failure and coronary artery disease had a stroke rate 3 times higher than patients without any risk factors. Patients with lone atria1 fibrillation <60 years old had no strokes. In patients 60-69 years old, there was a 1.6% incidence of stroke, compared with a 2.1% incidence of stroke in patients 70-79 years old. Finally, 25% of patients in the trials were women, in whom warfarin and aspirin decreased the risk of stroke by 84% and 23%, respectively.
atrial fibrillation.
(Adapted
from
CONCLUSION Nonrheumatic atria1 fibrillation, especially in the elderly, is a common cause of stroke. There have now been 6 major randomized clinical trials that have supported the use of anticoagulation in this population. A meta-analysis of the data from these trials has shown a 64% risk reduction for stroke in patients treated with warfarin compared with placebo. Atria1 fibrillation without concomitant risk factors or structural heart diseaseseem to confer little risk for stroke. The value of warfarin in patients > 75 years remains unclear because of a high risk of hemorrhagic complication. The use of the INR to guide warfarin therapy may help lower the rate of bleeding complications.2g Although these studies indicate the value of warfarin or aspirin for specific groups of patients we believe that therapy must be individualized; the data from these trials can only be used as a guide in management of this complex patient population. Figure 1 is a flow diagram that offers a suggestion as to how specific patient groups might be managed based on age and risk categories. The highest risk cohorts clearly benefit from warfarin. Those at lower risk need no therapy. Many future clinical trials will focus on those at intermediate risk to determine the best antithrombotic regimen and how to administer it for maximum efficacy and at minimal risk. Acknowledgment: We thank Roe Wells and Sheila Canovan for their assistancein the preparation of the manuscript. 1. Abbott W, Maloney RD, McCabe CC, Lee CE, Witthlin LS. Arterial embolism:a 44 year perspective./lm J Swg 1982;143:46OX4. 2. Kannel W, Abbott R, SavageD, McNamara P. Epidemiologic features of chronic atrial fibrillation: the Framingham Study. N Engl J Med 1982;317: 101&1022. 3. Cairns JA, Connolly SJ: Nonrheumatic atrial fibrillation: Risk of stroke and role of antithrombotic therapy. Circulation 1991;84:469-481. 4. Pritchett ELC. Management of atria1 fibrillation. N [email protected] A4ed1992;326: 1264-1271. 5. The National Heart, Lung, and Blood Institute Working Group on Atria1 Fibrillation. Atria1 fibrillation: current understandings and research imperatives,.I Am Co11Cardiol 1993,22:1930-1934. 6. Repique LJ, Shah SN, Marais GE. Atria1 fibrillation-1992 management strategiesin flux. Chesf1992;101:1095-1103, 7. Ezekowitz MD. Personalcommunication.
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20. Petersen P, Godtfredsen J. Embolic complications in paroxysmal atrial fibrillation. Stroke1986;17:622&?6. 21. Rokseth R, Storstein 0. Quinidiie therapy of chronic auricular fibrillation. Med 1992$16:1-5. 9.Kopec$ SL, Gersh BJ, McGcxxr MD, Whimant JP, Ilstrup DM. Lone Arch In&m Med 1963;111:18&189. 22. Petersen P, Boysen G, Godtfredsen J, Andersen CD, Andersen B, et al. atrial fibriiiation in the elderly. A population-based long term study. (Abstr.) PlacebocontroUed, randomized trial of warfarhi and aspirin for prevention of Circulation 1989;8O(suppl II):409. 10. Atwood J, AIbers G. Anticoagulation and atria1 fibrillation. Hm 1993;18: thromboembolic complication in chronic atria1 fibriiiation: the Copenhagen AFASAK study.Lancet 1989;1:175-178. 27-38. 23. The Boston Area Anticoagtdation Trial for Atria1 Fibrillation Investigators: 11. Atria1 Fibrillation Investigators. Risk factors for stroke and efficacy of The effect of low dose warfarin on the risk of stroke in patients with nonantithrombotic therapy in atriai fibrillation: analysis of pooled data from five rheumatic atrial fibrillation. N Engl JMed 199@3U:1505-1511 randomizedtrials. Arch Intent Med 1994;154:1449-1457. 24. Ezekowitz MD, Bridgers SL, JamesKE, Carlier Mt Coliiig CL, Gomick 12. Takahashi N, Seki A, Imataka K, Fujii J. Chnicai features of paroxysmal CC, Krause-Steinrauf H, Kurtzke JF, Nazarian SM, Radford MJ, Rickles FR, atriaI fibrillation: an observation of 94 patients.Jpn Heart J 1981;22:143-149. ShabetaiR, Deykin D, for the Veterans Affairs Stroke Prevention in Nonrheu13. Petersen P, Godtfredsen J. EmboIic complications in paroxysmal atria1 matic Atriai Fibrillation Investigators.The Veterans AtIairs Stroke Prevention fibrillation. Srroke1986;17:6%6’26. in Nonrheumatic Atria1 Fibrillation investigators:warfarin in the prevention of 14. Petersen P, Pedersen F, Johnson A, Madsen EB, Brun B, Boysen G, stroke associatedwith nonrheumatic atriai fibrillation. N Engl J Med 1992;327: Godtfredsen J. Cerebral computer tomographyon paroxysmalatria1SbriIlation. 1406-1412. 25.The Stroke Prevention in Atrial Fibrillation Study Group Investigators. Acta Neural Scand 1989;79:482-486. Stroke prevention in atria1 fibrillation study: final results. Circ&ion 1991;84: 15. Morris JJ Jr, Entman M, North WC, Kong Y, McIntosh H. The changesin cardiac output with reversion of atriai fibrillation to sinus rhythm. Cim*lation 527-539. 26. Stroke Prevention in Atria1 Fibrillation Investigators. Warf’arin vems aspi1%5;31:67CUi78. 16. Resnekov L, McDonald L, complications in 220 patients with cardiac rin for prevention of thromboembolismin atrial fibrillation: Stroke Prevention in Atria1 Fibrillation II Study.Lancet 1994;343:687-691. dysrhythmiastreated by phaseddiiect current shock,and indications for electro27. Connohy SJ, Laupacis A Gent M, Roberts RS, Cairns JA, Joyner C, for conversion.Br Heart J 196729926-936. the CAFA Study coinvestigators.Canadian Atria1 Fibrillation A&coagulation 17. Bjerkelund CT, Oming OM. The efficacy of autocoagulation therapy in (CAFA) study.JAm Co11Cardiol1991;18:349-355. preventing embolism related to DC. electricaI conversion of atriai fibrillation. 28. European Atria1 Fibrillation Trial Study Group. SecondaIy prevention in Am J G&o1 1969;23:208-216 non-rheumatic atriai fibrillation after ischaetnicattack or manor stroke. Lancet 18. Lown B, Perloth MG, Kaidbey S, Abe T, Harken DE. “Cardioversion” of 1993;342:1255-1262. atria1 fibrillation: a report on the treatment of 65 episodes in 50 patients. N 29.Andrews TC, Peterson DW, Doeppenschmidt D, Foster JS, Lucca MJ, Engl J Med 1%%269:325-331. Deering JA, LaVeau PJ. Complications of warfarin therapy monitored by the 19. Weinberg DM, Mancini GBJ. Anticoagulation for, cardioversion of atria1 International Normaliid Ratio versus prothrombii time ratio. Clin Cardiol fibrillation. Am J Cardiol1989;63:745-746. 1995;18:80-82. 8. Stroke Prevention in AtriaI Fibrillation Investigators.Predictors of thromboembolismin atria1fibrillation: I. Clinical features of patients at risk. Ann Intern
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THE AMERICAN JOURNAL OF CARDIOLOGY
VOLUME 77
JANUARY ‘25, 1996