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 atrialfibrillation (AF), the value of early antithrombotic therapy for AF patients with acute stroke has only recently 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).2–5Even
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
about treatment effects, but inclusion/exclusion criteria influ-ence the external validity of their results and must be examined carefully.
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 versusno 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 [email protected]
© 2002 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org DOI: 10.1161/01.STR.0000035735.49388.4A
2722
reported: the mean age was 78 years, 56% were women, and the 14-day and 6-month mortality rates were 17% and 39%,
respectively.2Symptomatic hemorrhagic transformation was
reported in 1% and was twice as frequent in AF participants
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.4There 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,4with 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 aspi(daltepa-rin 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.5Criteria 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.
Frequency of Early Recurrent
Ischemic Stroke
Early recurrent ischemic stroke appears to be slightly more frequent in acute stroke patients with AF than in those in
sinus rhythm.2,12,13In the IST, the reported rate of recurrent
ischemic stroke was 5% over 14 days among 1612 AF
participants not receiving heparin (half received aspirin).3
With allowance for a 20% reduction in early ischemic stroke recurrence by aspirin (see below), the rate of recurrent ischemic stroke in the absence of aspirin from the IST results is estimated as 6% over 2 weeks. The HAEST reported recurrent ischemic stroke within 2 weeks in 8% of 224 AF patients with acute stroke given aspirin (although some portion of these recurrences may have been nonthrombotic
worsening of the original deficit).5,14The CAST found a 5%
frequency of recurrent ischemic stroke over 4 weeks among
696 AF patients given aspirin.12 When the results from
participants receiving aspirin in these 3 clinical trials were 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,12yielding 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).12Hemorrhagic 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).12A 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
TABLE 1. Randomized Trials of Antithrombotic Therapy in Acute Stroke and AF*
Trial % Patients With AF/Mean Time to Treatment Interventions No. With AF IST2,3(1997) 17%/19 h 3169 Heparin 12 500 SC BID† 784 Heparin 5000 SC BID† 773 No heparin 1612 Aspirin 300 mg/d‡ 1622 No aspirin‡ 1547 CAST4(1997) 7%/25 h 1411 Aspirin 160 mg/d 696 Placebo 715 HAEST5(2000) 100%/21 h 449 LMW heparin 224 Aspirin 160 mg/d 225
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.
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-weightheparin versus aspirin (Table 2).5In 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
TABLE 2. Randomized Trials of Heparin or Aspirin in Acute Stroke With AF
Trial (Duration of Follow-Up) n
Recurrent Ischemic Strokes* Hemorrhagic Strokes All Strokes (Estimated) Good Outcome at 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
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.
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.18,21–24By 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,20stronger 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.6The use of tPA
within 3 hours of stroke doubled the likelihood of a favorable 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.25The 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.27The 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 disablingstrokes).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.30No 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.1,31In 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%.30Overall, 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).12In 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 aforemenobserva-tioned 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
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-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).4In a subsequent combined analysis that pooled
pa-tients from IST and CAST, the number of AF papa-tients 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.12Dr 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) method34was
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.
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