Comments, Opinions, and Reviews

Atrial Fibrillation, Stroke, and Acute

Antithrombotic Therapy
Analysis of Randomized Clinical Trials
Robert G. Hart, MD; Santiago Palacio, MD; Lesly A. Pearce, MS

Background—Strokes in patients with atrial fibrillation (AF) are typically larger, are associated with higher early
mortality, and occur in older patients versus strokes in patients with sinus rhythm. Until recently, the value of
antithrombotic therapies for acute stroke management has been based on empiric evidence.
Summary of Review—We present a critical review of 3 randomized clinical trials testing aspirin, heparin/heparinoid, or
both involving 5029 patients with AF and acute stroke. Early recurrent ischemic stroke occurred in about 5% of patients
during the 2 to 4 weeks after initial stroke. Data conflict about whether early use of heparin/heparinoid reduced early
recurrent ischemic stroke but are consistent regarding its lack of overall benefit on long-term functional outcome.
Modest benefits for reduction of early recurrent stroke and functional outcome were associated with aspirin use, based
largely on subgroup analysis from a single, large, unblinded trial.
Conclusions—No benefit of heparin has been demonstrated for acute stroke patients with AF; whether selected subgroups
would respond differently remains to be proven. Aspirin followed by early initiation of warfarin for long-term secondary
prevention is reasonable antithrombotic management. (Stroke. 2002;33:2722-2727.)
Key Words: aspirin 䡲 atrial fibrillation 䡲 heparin 䡲 stroke 䡲 thrombolysis

A lthough 1 of 6 ischemic strokes is associated with atrial

fibrillation (AF), the value of early antithrombotic
therapy for AF patients with acute stroke has only recently
about treatment effects, but inclusion/exclusion criteria influ-
ence the external validity of their results and must be
examined carefully.
Downloaded from http://ahajournals.org by on April 11, 2022

been clarified by randomized trials. Most ischemic strokes in
AF patients are due to cardiogenic embolism of left atrial
appendage thrombi. AF patients with stroke are typically
older (averaging approximately 75 years) with large hemi-
spheric strokes and with higher early mortality compared
with ischemic stroke patients in sinus rhythm.1,2 These
features, combined with the potential threat of early, recurrent
cardiogenic embolism and frequent spontaneous lysis of
cardioembolic occlusions, necessitate that the benefit versus
risk of antithrombotic therapies for acute stroke be examined
separately in AF patients.
In the 1980s and early 1990s, numerous case series and
case-control studies assessed the value of early heparin
anticoagulation in AF-associated stroke. Recent randomized
trials provide higher-quality evidence that should supplant
earlier observations as the basis for management decisions.
Outcomes in ⬎5000 patients with acute stroke and AF
randomized to heparin, low-molecular-weight heparin, or
aspirin in recent clinical trials are available (Table 1).2–5 Even
so, no clinical trial is perfect or answers all questions about all
issues, and relevant methodological aspects warrant scrutiny.
Randomized clinical trials yield the most reliable information
We critically analyze the benefits and risks of antithrom-
botic/fibrinolytic agents for AF patients with acute stroke on
the basis of data from all available randomized clinical trials
(AF patients have been included in several other recent
randomized trials in acute ischemic stroke, but outcomes in
AF patients have not been reported separately6 –11). The
implications of the trials’ results for the management of AF
patients with acute ischemic stroke are discussed.
Three Key Randomized Clinical Trials
In the International Stroke Trial (IST), 19 435 patients with
suspected acute ischemic stroke within 48 hours (93% con-
firmed as ischemic by early CT) at 467 hospitals were
randomly assigned to aspirin 300 mg/d versus no aspirin and,
separately, to 1 of 2 dosages of subcutaneous heparin versus
no heparin in a 2⫻3 factorial design (Table 1).3 Treatment
was not masked (ie, it was unblinded), and there were no
prespecified criteria for early recurrent stroke; both features
augmented the potential for biased determination of early
recurrent stroke. Functional outcomes after 6 months were
assessed mainly by participant questionnaire. Results for the
subgroup of 3169 participants (17%) with AF have been

Received March 5, 2002; final revision received May 21, 2002; accepted June 25, 2002.
From the Department of Medicine (Neurology), University of Texas Health Science Center, San Antonio (R.G.H., S.P.), and Minot, ND (L.A.P.).
Correspondence to Robert G. Hart, MD, Department of Medicine (Neurology), University of Texas Health Science Center, MSC 7883, 7703 Floyd
Curl Dr, San Antonio, TX 78229-3900. E-mail hartr@uthscsa.edu
© 2002 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org DOI: 10.1161/01.STR.0000035735.49388.4A

2722

TABLE 1. Randomized Trials of Antithrombotic Therapy in
Acute Stroke and AF*
% Patients With
AF/Mean Time to
Trial Treatment Interventions
IST2,3 (1997) 17%/19 h
Heparin 12 500 SC BID†
Heparin 5000 SC BID†
No heparin
Aspirin 300 mg/d‡
No aspirin‡
CAST4 (1997) 7%/25 h
Aspirin 160 mg/d
Placebo
HAEST5 (2000) 100%/21 h
LMW heparin
Aspirin 160 mg/d
LMW indicates low molecular weight.
*Other randomized trials included AF patients but did not report results
separately for this subgroup.
†Half received aspirin.
‡Half received heparin.
reported: the mean age was 78 years, 56% were women, and
the 14-day and 6-month mortality rates were 17% and 39%,
respectively.2 Symptomatic hemorrhagic transformation was
reported in 1% and was twice as frequent in AF participants
Downloaded from http://ahajournals.org by on April 11, 2022
as in those in sinus rhythm (P⬍0.05).
The Chinese Acute Stroke Trial (CAST) compared aspirin
160 mg/d with placebo (double-blind) in 21 106 patients with
suspected acute ischemic stroke within 48 hours (94% con-
firmed as ischemic by early CT) at 413 hospitals in China,
assessing outcomes after 4 weeks.4 There were apparently no
prespecified criteria for recurrent stroke. AF was present in
only 7% (n⫽1411) of participants (probably reflecting the
relatively low mean age of the stroke cohort). Limited data
about the subgroup of AF patients from the CAST have been
published,4 with additional outcome data available combining
AF patients assigned to aspirin in the CAST with those from
the IST (Appendix 1).
The Heparin in Acute Embolic Stroke Trial (HAEST) ran-
domly assigned 449 AF patients with acute ischemic stroke (all
confirmed by CT) within 30 hours of stroke onset from 45
Norwegian centers to a low-molecular-weight heparin (daltepa-
rin 100 IU/kg SC twice daily) or aspirin 160 mg/d in a
double-blind design, with the main outcomes of recurrent stroke
during the first 14 days and functional status or death after 3
months.5 Criteria for recurrent stroke included persistent wors-
ening of the original deficit after the first 48 hours; progressive
stroke was defined similarly except that it occurred within 48
hours of stroke onset and was more frequent than recurrent
stroke. The mean patient age was 80 years, and 55% were
women, with an 8% 14-day mortality rate and a 17% 3-month
mortality rate. Extracranial bleeding was significantly increased
in those assigned dalteparin, confirming an in vivo antithrom-
botic effect by the dosage used.
Hart et al Acute Stroke With Atrial Fibrillation 2723
Frequency of Early Recurrent
Ischemic Stroke
No. Early recurrent ischemic stroke appears to be slightly more
With frequent in acute stroke patients with AF than in those in
AF sinus rhythm.2,12,13 In the IST, the reported rate of recurrent
3169 ischemic stroke was 5% over 14 days among 1612 AF
784 participants not receiving heparin (half received aspirin).3
773
With allowance for a 20% reduction in early ischemic stroke
recurrence by aspirin (see below), the rate of recurrent
1612
ischemic stroke in the absence of aspirin from the IST results
1622
is estimated as 6% over 2 weeks. The HAEST reported
1547 recurrent ischemic stroke within 2 weeks in 8% of 224 AF
1411 patients with acute stroke given aspirin (although some
696 portion of these recurrences may have been nonthrombotic
715 worsening of the original deficit).5,14 The CAST found a 5%
449 frequency of recurrent ischemic stroke over 4 weeks among
696 AF patients given aspirin.12 When the results from
224
participants receiving aspirin in these 3 clinical trials were
225
combined, the rate of recurrent ischemic stroke within 2
weeks in AF patients was approximately 5%.
None of these 3 trials attempted to distinguish recurrent
ischemic stroke due to cardiogenic embolism from those due
to other mechanisms. When those with AF versus sinus
rhythm in the IST were compared, the frequency of recurrent
ischemic strokes was only slightly higher in AF patients, and
the relative risk reduction by aspirin was similar, suggesting
that many recurrences could have been noncardioembolic.3
Aspirin for Acute AF-Associated Stroke:
IST and CAST
Aspirin reduced early recurrent ischemic/unknown strokes by
approximately 25% in AF participants in the unblinded IST,3
with a smaller effect (5% reduction) in the double-blinded
CAST,12 yielding a combined relative risk reduction of 21%
(95% CI, ⫺5 to 41) (Table 2). Analysis confined to the
smaller number of CT-proven ischemic recurrent strokes
yielded a relative risk reduction of 30% (95% CI, ⫺4 to 53*)
(Appendix 2).12 Hemorrhagic stroke (including symptomatic
hemorrhagic transformation) occurred with nearly equal fre-
quency in those receiving aspirin versus no aspirin/placebo
(relative risk⫽1.0) (Table 2).12 The number of AF patients
who would need to be treated with aspirin to prevent 1
recurrent stroke over 2 to 4 weeks is approximately 100 on
the basis of the combined analysis of the IST and the CAST.12
The effect of aspirin on recurrent ischemic stroke among AF
participants in the IST and the CAST closely paralleled that
for the larger number in sinus rhythm, suggesting that the
observed reduction in AF patients may not necessarily have
been due to prevention of recurrent cardiogenic embolism.
All-cause mortality during the 2 to 4 weeks after stroke was
not reduced by aspirin versus control in the combined
analysis of the 2 trials (13%; relative risk⫽1.0; 95% CI, 0.8
to 1.2*) (Appendix 2), nor was the composite outcome of
recurrent stroke or death reduced (relative risk⫽1.0; 95% CI,
0.8 to 1.1).12 A small favorable trend by aspirin for reducing
death or dependency at 6 months among AF patients was
reported in the IST (22% of those treated with aspirin versus
20% of controls were alive and independent; relative risk of
good outcome⫽1.1; 95% CI, 0.9 to 1.3; P⫽0.20) (Table 2).3
 2724 Stroke November 2002

TABLE 2. Randomized Trials of Heparin or Aspirin in Acute Stroke With AF

Recurrent Ischemic Hemorrhagic All Strokes Good Outcome at
Trial (Duration of Follow-Up) n Strokes* Strokes (Estimated) 3– 6 mo
Atrial fibrillation
HAEST5 (14 d)
LMW heparin 224 19 (8%) 6 (25) 34%
Aspirin 225 17 (8%) 4 (21) 35%
IST2,3 (14 d)
Heparin 12 500 BID† 784 18 (2%)¶ 22 39 22%
Heparin 5000 BID† 773 26 (3%) 10 36 21%
No heparin† 1612 79 (5%) 7 86 21%
Aspirin‡ 1622 53 (3%) 22 75 22%
No aspirin‡ 1547 70 (5%) 17 87 20%
CAST4,12 (28 d)§
Aspirin 696 35 (5%) 17 (52) 䡠䡠䡠
Placebo 715 38 (5%) 20 (58) 䡠䡠䡠
Mixed cardioembolic sources
TOAST7 (7 d)㛳
LMW heparin 143 0 (0%) NR NR 48%
Placebo 123 2 (2%) NR NR 47%
FISS–bis15
LMW heparin 86 NR NR NR 22%
Placebo 62 NR NR NR 26%
CESG16 (14 d)
Heparin IV 24 0 (0%) 0 0 NR
No heparin 21 2 (10%) 0 2 NR
Downloaded from http://ahajournals.org by on April 11, 2022

LMW indicates low molecular weight; TOAST, Trial of Org 10172 in Acute Stroke Treatment; FISS– bis, Fraxiparine
in Ischemic Stroke Study; CESG, Cerebral Embolism Study Group; and NR, not reported.
*For IST and CAST, includes proven ischemic strokes plus unknowns.
†Half received aspirin.
‡Half received heparin.
§Personal communication, Z.M. Chen (Appendix 1).
㛳Approximately 40% with AF.
¶P⫽0.001 for reduction by heparin vs no heparin.

Heparin and Heparinoids for Acute
AF-Associated Stroke: IST and HAEST
Does the use of heparin/heparinoids reduce early recurrent
ischemic stroke in AF patients? Data from the 2 relevant
randomized clinical trials conflict. The double-blind HAEST
found no reduction in early recurrent ischemic stroke among
AF patients randomized to receive a low-molecular-weight
heparin versus aspirin (Table 2).5 In contrast, the IST found
“a clear and dose-dependent reduction in recurrent ischemic
stroke among patients allocated to heparin” (P⫽0.001) given
subcutaneously.2 The overall rates of recurrent ischemic
stroke in the control arms (5% in IST, 8% in HAEST) and of
secondary brain hemorrhage (2% in IST, 3% in HAEST)
among those given heparin/heparinoid were similar in the 2
trials. Potential explanations for the discrepant effects of
heparin/heparinoid on recurrent ischemic stroke include bi-
ased detection of events in the unblinded IST, a different
effect of the 2 specific agents, inclusion of nonthrombotic
causes of worsening among events in HAEST, the play of
chance, or a combination of these reasons. Taken at face
value, the trend toward a substantially larger reduction in
recurrent ischemic strokes by heparin among IST participants
with AF (44%) versus those in sinus rhythm (19%; P⫽0.09
for heterogeneity of odds ratio) supports an effect on early
recurrent cardiogenic embolism in AF patients.3
However, the reduction in early recurrent ischemic stroke by
heparin in the IST was almost entirely offset by increased
symptomatic brain hemorrhage: the frequency of recurrent
ischemic stroke combined with hemorrhagic stroke was approx-
imately 5% in both heparin arms and in those not receiving
heparin (risk reduction by heparin⫽10%; 95% CI, ⫺20 to 40).
Neither the IST nor the HAEST showed a benefit of anticoag-
ulation on functional outcome 3 to 6 months later, nor have other
randomized trials of low-molecular-weight heparins in patients
with mixed cardioembolic sources shown such benefit.7,8,15
Table 2 summarizes the results of randomized trials of heparin or
aspirin in acute stroke in patients with AF.2–5,7,12,15,16
Thrombolytic Therapy for Acute AF-Associated Stroke
AF patients have been modestly overrepresented in case
series and clinical trials of acute stroke patients treated with
 Hart et al
thrombolytic therapy: 20% to 30% of patients receiving
intravenous thrombolytic agents and almost half of those
undergoing intra-arterial thrombolysis have had AF.6,11,17–19
This increased prevalence is likely explained by the abrupt,
often dramatic, onset of major hemispheric deficits with
AF-associated stroke, prompting urgent evaluation within the
restricted time limits for thrombolytic therapy. Hypotheti-
cally, “old” thrombi from the left atrial appendage that
subsequently embolize could be relatively refractory to
thrombolysis; however, recanalization rates after tissue plas-
minogen activator (tPA) use appear to be high in AF
patients.18 –20 Given the generally larger volume of brain
infarction in AF patients with stroke, thrombolytic therapy
has been predictably associated with a higher likelihood of
symptomatic brain hemorrhage.18,21–24 By multivariate anal-
ysis with adjustment for extent and severity of ischemia, AF
was not independently associated with secondary brain hem-
orrhage after thrombolysis.21–24
While a recent case-control study reported improved out-
comes in AF patients with acute stroke treated with intrave-
nous tPA,20 stronger evidence is from subgroup analysis of
the randomized National Institute of Neurological Disorders
and Stroke (NINDS) tPA trial. The trial included 115 AF
patients with acute ischemic stroke (all confirmed by CT)
randomized to receive either intravenous tPA (0.9 mg/kg up
to 100 mg maximum) or placebo within 3 hours of stroke
onset, given double-blind, with the primary outcome func-
tional status assessed 6 months after stroke.6 The use of tPA
within 3 hours of stroke doubled the likelihood of a favorable
Downloaded from http://ahajournals.org by on April 11, 2022
outcome among all trial participants, but specific results for
the subgroup of AF patients have not been reported separate-
ly.25 There was no evident treatment interaction (P⫽0.96)
between a history of AF and benefit from tPA, but statistical
power to detect an interaction was limited.25 The focus of this
trial was on recovery from the initial ischemic deficit, and
effects on early recurrent ischemic stroke are not available.
The stakes are higher for thrombolytic treatment of AF
patients with stroke: the inherently worse prognosis of AF-
associated stroke accentuates both the risks and potential
benefits of intravenous tPA. Many AF patients with stroke are
elderly, but age alone does not appear to be a contraindication
for the use of intravenous tPA.26 Additional data about the
efficacy and safety of thrombolysis in larger numbers of AF
patients with acute stroke, and particularly those aged ⬎75
years with large strokes, would be reassuring.27 The value of
intra-arterial thrombolysis specifically in AF patients cannot
be determined from the published literature.
Subgroups of AF Patients Defined by
Mechanism, Stroke Size, Presence of Left
Atrial Thrombi, or Other Factors
On the basis of current concepts of ischemic stroke mecha-
nisms in AF, predictors of early recurrent embolism, and risk
factors for hemorrhagic worsening during anticoagulation,
subgroups of AF patients who could respond differently to
acute antithrombotic therapy can be postulated. Perhaps 25%
of ischemic strokes in AF patients are noncardioembolic, and
the effects of acute antithrombotic therapy may differ in this
subset (which tends to suffer smaller, less disabling
Acute Stroke With Atrial Fibrillation 2725
strokes).28 Transesophageal echocardiography demonstrates
left atrial appendage thrombus in approximately 25% of AF
patients with prior stroke and in 10% of those without prior
clinical stroke, but the prognostic value for proximate embo-
lization has not been defined (the observation that AF patients
without clinical embolism demonstrate appendage thrombi
suggests that thrombi visualized by transesophageal echocar-
diography do not always pose an immediate threat). Hemo-
static abnormalities may predict early recurrent strokes.29
Larger infarcts are more prone to symptomatic hemorrhagic
worsening caused by antithrombotic and fibrinolytic thera-
pies; small infarcts could favorably shift the balance of
benefit and risk of heparin on the basis of the IST results (but
are of no consequence on the basis of the HAEST results).
The interval from stroke onset to treatment with heparin/hep-
arinoid averaged approximately 20 hours in the available
randomized trials; early initiation of heparin within 6 hours
has been associated with improved outcome in a clinical case
series.30 No subgroup data from existing randomized trials are
available, and hence the relevance of these AF subgroups to
immediate antithrombotic management remains speculative.
Are the Key Randomized Trials Applicable to
Clinical Practice?
Recent multicenter surveys of AF patients hospitalized for
acute ischemic stroke in Europe and in the United States
reported mean patient ages of 75 to 77 years, percentages of
women of 50% to 60%, inpatient mortality rates of 18% to
19%, and a mortality rate of 33% after 3 months.1,31 In a large
clinical case series of AF patients treated with intravenous
heparin, the mean age was ⬎70 years and early mortality was
9%, with rates of recurrent ischemic stroke of 2% and
symptomatic hemorrhagic stroke of 3%.30 Overall, these are
similar to the features of AF participants in the IST and the
HAEST. No specific data are available for AF participants in
the CAST, although the estimated early mortality among AF
patients appears to be relatively low (10% to 12% during the
first month).12 In summary, AF patients enrolled in the IST
and the HAEST appear generally representative of AF pa-
tients with stroke from hospital-based surveys; no informa-
tion is available about AF participants in the CAST.
Summary and Conclusions
Early recurrent ischemic stroke occurred in approximately
5% of AF patients during the initial 2 weeks in recent
randomized trials, but it is unclear whether most were
cardioembolic. This analysis began with the premise that AF
patients with acute ischemic stroke may respond differently
to antithrombotic therapies. However, when randomized tri-
als that included both patients with AF and patients with sinus
rhythm (IST and CAST) were considered, the relative effects
of antithrombotic therapy were not importantly different
between AF patients and the larger number of patients in
sinus rhythm. The mechanistic implications of this observa-
tion are undetermined because of the aforementioned vagar-
ies of the trial designs, but the clinical implications are more
clear.
Whether heparin/heparinoids reduce recurrent ischemic
stroke (and recurrent cardiogenic embolism) in AF patients is
 2726 Stroke November 2002
uncertain because of the conflicting results of the HAEST and
the IST, but overall rates of recurrent stroke (ie, ischemic and
hemorrhagic combined) and functional outcome are not
improved by the use of these agents. Some have argued that
early treatment with intravenous, adjusted-dose heparin (not
yet tested in randomized trials) would be more efficacious,32
but this remains to be established.
With the caveat of potentially biased event detection in
IST, analysis of 4551 AF patients randomized to aspirin
versus control in the IST and the CAST treated a mean of
approximately 20 hours after stroke onset shows trends
toward modest reduction in early recurrent stroke and toward
improved 6-month functional outcome. Given these trends
combined with the safety and ease of use of aspirin, early
aspirin therapy is sensible for AF patients with acute ischemic
stroke (combined with low-dose subcutaneous heparin for
prevention of venous thrombosis if substantial leg weakness
is present).
The fraction of AF patients with good outcomes 6 months
after stroke is distressingly small, emphasizing the impor-
tance of stroke prevention and the need for more efficacious
acute interventions. Intravenous tPA given within 3 hours of
stroke onset appears to offer the most potential benefit for AF
patients with acute ischemic stroke; however, this is based on
limited information about 115 AF patients in the NINDS tPA
trial, and more data are needed to be confident of the effect in
AF patients.
When should warfarin be initiated for secondary preven-
tion? Warfarin anticoagulation is highly efficacious for long-
Downloaded from http://ahajournals.org by on April 11, 2022
term secondary prevention in AF patients, but there is a
paucity of data addressing when warfarin can be safely
initiated after stroke. In the European Atrial Fibrillation Trial,
approximately 100 AF patients commenced oral anticoagu-
lation within 2 weeks of ischemic stroke or transient ischemic
attack, and there was no reported secondary hemorrhagic
worsening (however, AF patients with large, disabling
strokes that are prone to hemorrhagic transformation were
underrepresented in this trial).33 On the basis of the usual
timing of secondary hemorrhagic transformation between 12
hours and 4 days after stroke onset, it seems reasonable to
begin warfarin as soon as the patient is medically and
neurologically stable, often 2 to 3 days after stroke, to achieve
therapeutic anticoagulation 7 to 10 days after stroke onset.
Some experts routinely repeat a CT scan before initiating
warfarin and delay warfarin therapy if hemorrhagic transfor-
mation is evident. Minor degrees of hemorrhagic transforma-
tion are frequent (particularly on MRI), and the clinical
significance regarding initiation of warfarin is unclear and
controversial. Empirically, we repeat a CT scan before
initiating warfarin if there is clinical worsening, if the infarct
is large, or in the presence of undue headache, delaying
initiation of warfarin for 1 week if substantial hemorrhage is
evident.
Appendix 1
Data on Recurrent Stroke From CAST
The main CAST results publication reported only the number of
patients with death or nonfatal (confirmed) ischemic strokes in AF
participants assigned to aspirin versus placebo (99 versus 111,
respectively).4 In a subsequent combined analysis that pooled pa-
tients from IST and CAST, the number of AF patients with recurrent
ischemic stroke was given as 46 versus 64 on aspirin versus no
aspirin/placebo, but this was restricted to CT-confirmed recurrent
ischemic strokes.12 Dr Z.M. Chen of the CAST reanalyzed the data
and reported that when CT-confirmed and unknown strokes were
combined (to be comparable with the IST report3), recurrent ische-
mic strokes among AF participants occurred in 35 versus 38 on
aspirin versus placebo, respectively (Z.M. Chen, written personal
communication, January 2, 2002). The number of hemorrhagic
strokes in the CAST was obtained by subtracting the IST patients3
from the combined total.12
Appendix 2
Statistical Methods
Meta-analyses of the trials are presented as relative risk reductions
for treatment groups compared with control groups. To estimate the
relative risk reduction, the combined odds ratio estimate computed
with the use of the modified Mantel-Haenszel (Peto) method34 was
subtracted from 1. Before risk reduction was estimated, the assump-
tion of statistical homogeneity of treatment effect (across trials and
within a specific scenario) was tested with the use of the QsubL
statistic for the relative odds scale,35 with lack of homogeneity
precluding estimation of overall treatment effect (probability values
are reported only if ⬍0.2). Estimates of relative risk reduction in
individual trials were computed by subtracting the estimated odds
ratio from 1. Meta-analysis results to estimate relative risk reduction
in which only combined data were reported (ie, individual trial data
were not available) are indicated by an asterisk (*), and relative risk
reduction was calculated as if data were from a single trial.
References
1. Lamassa M, Di Carlo AA, Pracucci G, Basile AM, Trefoloni G, Vanni P,
Spolveri F, Baruffi MC, Landini G, Ghetti A, Wolfe CDA, Inzitari D.
Characteristics, outcome, and care of stroke associated with atrial fibril-
lation in Europe: data from a multicenter multinational hospital– based
registry (The European Community Stroke Project). Stroke. 2001;32:
392–398.
2. Saxena R, Lewis S, Berge E, Sandercock PAG, Koudstaal PJ, for the
International Stroke Trial Collaborative Group. Risk of early death and
recurrent stroke and effect of heparin in 3169 patients with acute ischemic
stroke and atrial fibrillation in the International Stroke Trial. Stroke.
2001;32:2333–2337.
3. International Stroke Trial Collaborative Group. The International Stroke
Trial (IST): a randomized trial of aspirin, subcutaneous heparin, both, or
neither among 19435 patients with acute ischemic stroke. Lancet. 1997;
349:1569 –1581.
4. CAST (Chinese Acute Stroke Trial) Collaborative Group. CAST: ran-
domized placebo-controlled trial of early aspirin use in 20,000 patients
with acute ischemic stroke. Lancet. 1997;349:1641–1649.
5. Berge E, Abdelnoor M, Nakstad PH, Sandset PM, for the HAEST Study
Group (Heparin in Acute Embolic Stroke Trial). Low molecular-weight
heparin vs. aspirin in patients with acute ischemic stroke and atrial
fibrillation: a double blind randomised study. Lancet. 2000;355:
1205–1210.
6. National Institute of Neurological Disorders and Stroke rt-PA Stroke
Study Group. Tissue plasminogen activator for acute ischemic stroke.
N Engl J Med. 1995;333:1581–1587.
7. Publications Committee for the Trial of ORG 10172 in Acute Stroke
Treatment (TOAST) Investigators. Low molecular weight heparinoid,
ORG 10172 (danaparoid), and outcome after acute ischemic stroke.
JAMA. 1998;279:1265–1272.
8. Bath PMW, Lindenstrom E, Boysen G, De Deyn P, Friis P, Leys D,
Marttila R, Olsson JE, O’Neill D, Orgogozo JM, Ringelstein B, van der
Sande JJ, Turpie AGG, for the TAIST Investigators. Tinzaparin in acute
stroke (TAIST): a randomized, aspirin-controlled trial. Lancet. 2001;358:
702–710.
9. Diener H, Ringelstein EB, von Kummer R, Langohr HD, Bewermeyer H,
Landgraf H, Hennerici M, Welzel D, Grave M, Brom J, Weidinger G, for
the Therapy of Patients with Acute Stroke (TOPAS) Investigators.
Treatment of acute ischemic stroke with the low-molecular-weight
heparin certoparin: results of the TOPAS trial. Stroke. 2001;32:22–29.
 Hart et al
10. Duke RJ, Bloch RF, Turpie AGG, Trebilcock R, Bayer N. Intravenous
heparin for the prevention of stroke progression in acute partial stable
stroke: a randomized controlled trial. Ann Intern Med. 1986;105:
825– 828.
11. Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D,
Larrue V, Bluhmki E, Davis S, Donnan G, Schneider D, Diez-Tejedor E,
Trouillas P. Randomized double-blind placebo-controlled trial of
thrombolytic therapy with intravenous alteplase in acute ischaemic stroke
(ECASS II). Lancet. 1998;352:1245–1251.
12. Chen ZM, Sandercock P, Pan HC, Counsell C, Collins R, Liu LS, Xie JX,
Warlow C, Peto R, on behalf of the CAST and IST Collaborative Groups.
Indications for early aspirin use in acute ischemic stroke: a combined
analysis of 40,000 randomized patients from the Chinese Acute Stroke
Trials and the International Stroke Trial. Stroke. 2000;31:1240 –1249.
13. Moroney JT, Bagiella E, Paik MC, Sacco RL, Desmond DW. Risk factors
for early recurrence after ischemic stroke. Stroke. 1998;29:2118 –2121.
14. Toni D, Argentino C, Fieschi C. Heparin versus aspirin in ischaemic
stroke. Lancet. 2000;356:504 –505.
15. Bath PMW, Iddenden R, Bath FJ. Low-molecular-weight heparins and
heparinoids in acute ischemic stroke: a meta-analysis of randomized
controlled trials. Stroke. 2000;31:1770 –1778.
16. Cerebral Embolism Study Group. Immediate anticoagulation of embolic
stroke: a randomized trial. Stroke. 1983;14:668 – 676.
17. Albers GW, Bates VE, Clark WM, Bell R, Verro P, Hamilton SA.
Intravenous tissue-type plasminogen activator for treatment of acute
stroke. JAMA. 2000;283:1145–1150.
18. Liebeskind DS, Saver JL, Duckwiler GR, Kidwell CS, Carneado J,
Starkman S, Vespa PM, Gobin P, Jahan R, Kasner SE, Vinuela F. Atrial
fibrillation and intra-arterial thrombolysis. Stroke. 2001;32:370. Abstract.
19. Yoneda Y, Mori E, Uehara T, Tabuchi M. Non-valvular atrial fibrillation
in acute ischaemic stroke candidates for thrombolytic therapy. Cere-
brovasc Dis. 1997;7:357–358.
20. Molina C, Alvarez-Sabin J, Montaner J, Abilleira S, Arenillas J, Codina A.
Timing of thrombolysis-induced recanalization in acute cardioembolic stroke: a
case-control study. Cerebrovasc Dis. 2001;11(suppl 4):120. Abstract.
21. Jaillard A, Cornu C, Durieux A, Moulin T, Boutitie F, Lees KR, Hommel
M. Hemorrhagic transformation in acute ischemic stroke: the MAST-E
Study. Stroke. 1999;30:1326 –1332.
Downloaded from http://ahajournals.org by on April 11, 2022
22. Larrue V, von Kummer R, del Zoppo G, Bluhmki E. Hemorrhagic
transformation in acute ischemic stroke: potential contributing factors in
the European Cooperative Acute Stroke Study. Stroke. 1997;28:957–960.
Acute Stroke With Atrial Fibrillation 2727
23. NINDS tPA stroke Study Group. Intracerebral hemorrhage after intrave-
nous t-PA therapy for ischemic stroke. Stroke. 1997;28:2109 –2118.
24. Tanne D, Demchuk A, Kasner SE, Grond M, Hanson S, Hamilton S,
Buchan AM, Wang DZ, Wechsler LR, Zweifler R, Levine SR. A large
multinational investigation to predict t-PA related symptomatic ICH in
patients with acute ischemic stroke. Stroke. 1999;30:248. Abstract.
25. NINDS t-PA Stroke Study Group. Generalized efficacy of t-PA for acute
stroke: subgroup analysis of the NINDS t-PA Stroke Trial. Stroke. 1997;
28:2119 –2125.
26. Tanne D, Gorman MJ, Bates VE, Kasner SE, Scott P, Verro P, Binder JR,
Dayno JM, Schultz L, Levine SR, and the tPA Stroke Survey Group.
Intravenous tissue plasminogen activator for acute ischemic stroke in
patients aged 80 years and older. Stroke. 2000;31:370 –375.
27. Brott TG, Kaste M, Albers GW. Analysis of the NINDS, ECASS I and
ECASS II and Atlantis Data Sets. Paper presented at: 27th International
Stroke Conference; February 9, 2002; San Antonio, Tex.
28. Hart RG, Pearce LA, Miller VT, Anderson DC, Rothrock JF, Albers GW,
Nasco E. Cardioembolic vs. noncardioembolic stroke in atrial fibrillation:
frequency and effect of antithrombotic agents in the Stroke Prevention in
Atrial Fibrillation studies. Cerebrovasc Dis. 2000;10:39 – 43.
29. Yonemura K, Yasaka M, Kimura K, Minematsu K, Yamaguchi T. Pre-
disposing factors of early recurrent embolism in stroke patients with
nonvalvular atrial fibrillation. Stroke. 2002;33:348. Abstract.
30. Chamorro A, Vila N, Ascaso C, Blanc R. Heparin in acute stroke with
atrial fibrillation: clinical relevance of very early treatment. Arch Neurol.
1999;56:1104 –1108.
31. Albers GW, Bittar N, Young L, Hattemer CR, Gandhi AJ, Kemp SM,
Hall EA, Morton DJ, Yim J, Vlasses PH. Clinical characteristics and
management of acute stroke in patients with atrial fibrillation admitted to
US university hospitals. Neurology. 1997;48:1598 –1604.
32. Chamorro A. Immediate anticoagulation in acute focal brain ischemia
revisited: gathering the evidence. Stroke. 2001;32:577–578.
33. EAFT (European Atrial Fibrillation Trial) Study Group. Secondary pre-
vention in nonrheumatic atrial fibrillation after TIA or minor stroke.
Lancet. 1993;342:255–262.
34. Berlin JA, Laird NM, Sacks HS, Chalmers TC. A comparison of sta-
tistical methods for combining event rates from clinical trials. Stat Med.
1989;8:141–151.
35. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin
Trials. 1986;7:177–188.