原Early 著

or Delayed Anticoagulation in Patients with Atrial Fibrillation Upon Acute Ischemic Stroke: A Systematic Review and Meta-Analysis

Early or Delayed Anticoagulation in Patients with Atrial

Fibrillation Upon Acute Ischemic Stroke: A Systematic
Review and Meta-Analysis
Yen-Ling Lo1, Hsin-Hsi Tsai1, 2, Li-Kai Tsai1, 3
1
Departments of Neurology, National Taiwan University Hospital, Taipei, Taiwan.
2
Departments of Neurology, National Taiwan University Hospital Bei-Hu Branch, Taipei, Taiwan.
3
Departments of Neurology, National Taiwan University Hospital Hsinchu Branch, Hsinchu, Taiwan.

ABSTRACT
Background: The optimal timing to initiate oral anticoagulation in acute ischemic stroke for patients
with atrial fibrillation (AF) remains undetermined. This meta-analysis aims to investigate the effectiveness
and safety between early and delayed use of oral anticoagulation after acute ischemic stroke in patients with
AF.
Method: Relevant literature was collected from the PubMed and Scopus electronic database platforms.
4 randomized controlled trials (RCTs) and 7 observational studies from 204 articles were included for meta-
analysis. We compared the incidence of recurrent ischemic stroke, intracranial hemorrhage and composite
outcomes between those receiving early or delayed anticoagulation.
Results: In RCTs and observational studies of 8,874 patients with AF upon acute ischemic stroke, early
initiation of NOACs or warfarin showed significant reduction in composite outcome using the random-
effects model (relative risk [RR]: 0.75; 95% confident interval [CI]: 0.58-0.96) as compared to delayed
administration of anticoagulants. In 10,743 patients, early anticoagulation led to significant reduction in
recurrent ischemic stroke (RR: 0.72; 95% CI: 0.51-0.91) than delayed anticoagulation. On the other hand, in
10,002 patients with AF, there was no significant difference in the risk of intracranial hemorrhage between
two groups (RR: 0.91; 95% CI: 0.67-1.22). To restrict the analysis on two large high-quality RCTs with
total 2,901 patients, early anticoagulation with NOACs showed a trend toward lower risk to develop events
of composite outcome than late administration of NOACs (RR: 0.75; 95% CI: 0.54-1.04).
Conclusion: In patients with AF-related acute ischemic stroke, our meta-analysis demonstrated that
early initiation of anticoagulation is superior than delayed administration in reducing composite outcome
and recurrent ischemic strokes without increasing on the risk of intracranial hemorrhage.

Keywords: Atrial fibrillation, early, ischemic stroke, intracranial hemorrhage, anticoagulants.

Introduction 0.51%, respectively. 1, 2 AF increases the risk of

stroke by five times, and approximately 20% of
The prevalence of atrial fibrillation (AF) all strokes are linked to AF. 3 Survivors of AF-
in Taiwan and all over the world are 1.1% and related stroke tend to experience more significant

Corresponding author: Hsin-Hsi Tsai, MD, PhD, Departments of Neurology and Stroke Center, National Taiwan University
Hospital, Taipei, Taiwan.
E-mail: tsaihsinhsi@gmail.com
DOI: 10.6318/FJS.202403_6(1).0004

72
 Early or Delayed Anticoagulation in Patients with Atrial Fibrillation Upon Acute Ischemic Stroke: A Systematic Review and Meta-Analysis
disability and face an increased risk of recurrent
strokes compared to patients with other stroke
causes.4, 5 For patients with AF, warfarin, a vitamin
K antagonist, has been found to reduce the risk of
stroke by about 60%. Non-vitamin K antagonist
oral anticoagulants (NOACs) selectively inhibit
thrombin or activated factor X, presenting potential
6, 7
benefits compared to warfarin.
current guidelines from the Taiwan Stroke Society
(TSS) and the American Heart Association/
American Stroke Association (AHA/ASA) suggest
to use NOACs or warfarin for secondary stroke
prevention for AF patients with elevated risks of
8, 9
stroke.
Anticoagulation therapy decreases the chance
of recurrent stroke and systemic embolism, but
it also elevates the risk of cerebral hemorrhage
especially during the acute phase following
an ischemic stroke in AF patients. 8 In clinical
practice, the timing for initiating anticoagulants
upon acute ischemic stroke in patients with AF
is an important issue. However, the optimal
timing to start anticoagulants for AF patients
with acute ischemic stroke is still unclear. The
Guideline of the TSS suggests the “1-3-6-12”
rule for starting anticoagulant treatment primarily
based on expert opinions. 9 The 2021 guideline
from the AHA/ASA suggests that patients with
large cerebral infarction might have a greater risk
of hemorrhagic transformation; the initiation of
oral anticoagulation after stroke onset at 14-day
delay is only moderately recommendated. There
have been increasing observation studies and
randomized controlled trials addressing the optimal
timing of initiating anticoagulation after stroke.
In the absence of clear and uniform guideline
recommendations, we endeavored to address
this clinically unsettled issue by undertaking a
systematic literature review and meta-analysis that
incorporates the latest studies available.
Methods
Search methodology
We searched PubMed and Scopus database
Therefore, between June 1985 to May 2023 using a
combination of search terms: (atrial fibrillation)
AND ((early) OR (delay)) AND (anticoagulant)
AND ((ischemic stroke) OR (ischaemic stroke))
AND ((intracranial hemorrhage) OR (intracerebral
hemorrhage)).
Studies were eligible for (1) published in
English; (2) were randomized controlled trials
(RCTs) or observation studies that evaluated the
timing of NOAC or warfarin initiation and their
effects on composite outcomes (recurrent ischemic
stroke, transient ischemic attack [TIA], systemic
embolism, major bleeding, intracranial hemorrhage
[ICH], and/or vascular death) in patients with AF
and acute ischemic stroke. We excluded review
articles and studies in which title and abstract are
incompatible with keywords.
Data extraction and risk of bias
assessment
Studies were screened focusing on titles and
abstracts to recognize suitable articles for full-
text assessment by two reviewers (author Y-L.L.
and L-K.T.). We used a spreadsheet to collected
8
the following information: authors; country
of origin; study design; median age; type and
number of participants; initiation time of NOACs/
warfarin; follow-up time, composite outcomes and
secondary outcome including recurrent ischemic
stroke and ICH. We collected data from RCTs
and observational studies in accordance with the
Preferred Reporting Items for Systematic Reviews
73
 Early or Delayed Anticoagulation in Patients with Atrial Fibrillation Upon Acute Ischemic Stroke: A Systematic Review and Meta-Analysis

and Meta-Analysis (PRISMA) statement.
The Cochrane risk of bias tool for RCT
studies was evaluated using the danger of bias tool
that encompasses six domains of bias: selection
bias, performance bias, detection bias, attrition
bias, reporting bias, and publication bias. The bias
was appraised by funnel plots of study results
plotted against participant size using Review
Manager5.
follow-up period using the random-effects model.
To assess the overall heterogeneity, I 2 test was
utilized with I2 statistic. I2 25%, 50%, and 75%
indicates low, moderate and high heterogeneity,
respectively.10 P-value < 0.05 was considered as
statically significant.
Results

The process of data synthesis and Included studies

statistical analysis
Data were examined by R version 4.3.1
software with meta package. We pooled risk
ratio (RR) and 95% confidence intervals (CI) of
composite and secondary outcomes over 30-day
A search conducted on the PubMed and
Scopus databases resulted in a collection of 204
studies. A PRISMA flow diagram is displayed
in Figure 1. Consequently, four RCTs and seven
observational studies were included for further

Figure 1. PRISMA 2020 flow diagram for systematic reviews.

74
 Early or Delayed Anticoagulation in Patients with Atrial Fibrillation Upon Acute Ischemic Stroke: A Systematic Review and Meta-Analysis
meta-analysis.11-21
The summary of four RCT studies is presented
in Table 1. In a total of 3,172 participants (female,
11-14
40.9% to 63.4%; mean age, 70 to 78 years),
the definition of early and delayed administration
of anticoagulants was different across RCTs. Two
of them sub-grouped the administration time
12,
according to clinical stroke severity or infarct size
14
. In two studies comparing the outcomes between
anticoagulation using NOACs and warfarin, we
considered the NOAC arm to be early treatment
group and the warfarin arm to be delayed treatment
group since the peak plasma levels are achieved
within 4 hours after NOAC while after 5 days after
warfarin administration. In quality assessment, the
category of “blinding participants and personnel”
showed a high risk of bias in which two studies
were designed to be open-labeled and the other two
were single masking. Other categories presented
as low bias risk including random sequence
generation, allocation concealment, blinding of
outcome assessment, incomplete outcome data,
and selective reporting.
The characteristics of seven observational
studies were presented in Table 2.15-21 In a total of
7,756 participants (female, 30.6% to 62%; mean
age, 64.5 to 80 years), the primary outcomes were
composite events including recurrent ischemic
stroke, TIA, systemic embolism, major bleeding,
ICH, and/or cerebrovascular death. These studies
also had varying definitions for the early and
delayed administration of anticoagulants.
Composite outcome comparisons
between early vs. delayed
initiation of OAC
The result of early treatment group (n = 4,097)
was compared to that from delayed treatment group
(n = 4,777) in 8,874 participants with AF who had
experienced acute ischemic stroke in eligible 7
of 11 studies. In the random effects model, early
anticoagulation showed significantly lower risk of
composite outcome than delayed anticoagulation
(RR: 0.75; 95% CI: 0.58-0.96) (Figure 2). The
heterogeneity was low with heterogeneity I2 of
33% (P = 0.18).
When focusing on four RCTs with 3,172
participants, early administration of anticoagulants
showed an insignificant trend toward lower risk
than delayed administration of composite outcome
(RR:0.83; 95% CI: 0.67-1.01) (Figure 2). The
heterogeneity was low with heterogeneity I 2 of
0% (P = 0.77). We also conducted an analysis on
only two large high-quality RCTs assessing early
vs. delayed initiation of NOAC.13,14 The early
treatment group (n = 1,456) showed non-significant
decreases in the composite outcome (RR: 0.75;
95% CI: 0.54-1.04) than delayed treatment group (n
= 1,445) and there was low heterogeneity with I2
of 0% (P = 0.73).
Three of the 7 observational studies were
eligible for analyses of composite outcome.
Patients receiving early anticoagulants treatment
(n = 2,505) showed significantly lower risk of
composite outcome than those receiving delayed
treatment (n = 3,197) (RR: 0.63; 95% CI: 0.32-
1.24) (Figure 2). Meaningful heterogeneities were
observed across these observational studies (I2 =
70%, P = 0.03).
Risk of recurrent ischemic
stroke between early vs. delayed
initiation of OAC
Ten of the 11 studies (n = 10,744) were
eligible to compare the risks for recurrent ischemic
stroke between early (n = 5,292) and delayed
(n = 5,452) treatment groups (Figure 3). The
heterogeneity was low with I2 of 15% (P = 0.31).
75
76
Table 1. Summary of four randomized controlled trials
Author Country Trial Study Type of Sample size(% Initiation time of Primary Conclusion
(year) allocation participants female) and medication(Stroke severity) composite
ratio and mean age outcome (time,
masking poststroke)
Hong et South Triple 1:1, open Mild AIS 95 (42.1) vs. Early: rivaroxaban ICH/ recurrent No differences in the
al., 2017 Korea AXEL label within 5 days 88 (40.9); < 5 days after AISD IS (30 days) primary composite
with AF 70.4 years elayed: warfarin, outcome (49.5% vs
< 5 days after AIS 54.5%; P = 0.49).
Labovitz et USA AREST 1:1, open AIS within 3–5 41 (63.4) vs. Early: apixaban Recurrent IS, Similar outcome
al., 2021 label days or TIA 47 (48.9); Day 0-3 after TIA TIA, and fatal between two groups
within 3 days 73.5 years Day 3-5 after small-sized stroke (180 with the risk of
with AF AIS days) primary composite
Day 7-9 after medium- outcome of 17.1% and
sized AIS 25.5% (P=0.44).
Delayed: warfarin
> 7 days
Oldgren et Sweden TIMING 1:1, single AIS within 72 450 (46) vs. Early: NOAC, ≦4 days Recurrent IS, Early initiation was
al., 2022 (outcomes hours with AF 438 (46.3); Delayed: NOAC, 5-10 days symptomatic noninferior to delayed
assessor) 78.3 years intracerebral start of NOAC with
hemorrhage, nonsignificant lower
or all-cause rates of composite
mortality (90 outcome (OR:
days) 0.78 [0.48-1.25]);
no symptomatic
intracerebral
hemorrhage in each
group.
Fischer et Switzerland ELAN 1:1, single AIS lasting 1006 (45.6) vs. Early: NOAC Major A trend toward lower
al., 2023 (outcomes more than 24 1007 (45.3); < 2 days after minor or bleeding, risk of composite
assessor) hours with AF 77 years moderate AIS recurrent outcome in early than
Day 6 or 7 after major AIS IS, systemic later anticoagulation
Delayed: NOAC embolism and/ groups (OR: 0.7
Day 3 or 4 after minor AIS or vascular [0.44-1.14]); only 2
Day 6 or 7 after moderate death (30 days) symptomatic ICH
AIS occurred in each group
Day 12-14 after major AIS (0.2%)
Early or Delayed Anticoagulation in Patients with Atrial Fibrillation Upon Acute Ischemic Stroke: A Systematic Review and Meta-Analysis

AF indicates atrial fibrillation; AIS, acute ischemic stroke; ICH, intracranial hemorrhage; IS, ischemic stroke; NOAC, non-vitamin K antagonist oral anticoagulant;
OR, odds ratio; TIA, transient ischemic attack.
 Table 2. Summary of seven observational studies

Author Country Study design Type of Sample size Initiation time of medication Outcome (time, post- Conclusion
(year) participants (% female; (Stroke severity) stroke)
mean age)
Cappellari Italy Prospective Stroke 97 (61.8) Early: NOACs 1-3 days ICH and recurrent IS (7 No link between starting
et al., 2016 observational with non- 50 (62); Delayed: NOACs 4-7 days days) NOACs early and ICH
valvular AF 79 years
Wilson et UK Prospective AF with 358 (43) Early: NOACs ≤4 days Recurrent IS, TIA, ICH, Composite outcome 2% vs
al., 2019 observational acute 997 (41); Delayed: NOACs ≥ 5 days or death due to any cause 5% (no difference)
ischemic 76 years (90 days)
stroke/TIA
Yaghi et USA Retrospective AF with 862 (50.3) Early: NOACs median 5 Recurrent ischemic event Early NOAC treatment
al., 2020 observational acute 389 (49.4); days and symptomatic ICH associated with less infarct
ischemic 76-78 years Delayed: warfarin median 2 (90 days) and similar ICH risk
stroke days
D'Anna et Germany Retrospective AF with 300 (46) Early: NOACs 7 ± 9.4 days Major (intracranial and Using NOACs within 7 days
al., 2020 observational acute 259 (44.4); Delayed: warfarin 11.9 extracranial) bleeding, are safe in both extracranial
ischemic 80 years ±19.7 days Recurrent IS, TIA and and intracranial bleeding
stroke mortality (16 days) complications.
Bakr et al., Saudi Arabia Retrospective AF with 55 (50) Early: NOACs or warfarin Recurrent IS and ICH (90 Higher risk of intracerebral
2020 observational acute 42 (30.6); 1~6 days to 180 days) hemorrhage in early
ischemic 64.5 years Delayed: NOACs or treatment group
stroke/TIA warfarin 7~14 days
Kimura et Japan Prospective AF with 785 (40) Early: NOACs,≦1 (TIA), Recurrent IS, systemic Early initiation of
al., 2022 observational acute 1012 (41); ≦2 (minor), ≦3 (mod), embolism, severe NOACs reduces the risk
ischemic 77 years ≦4 (severe) bleeding, and death (90 of recurrence stroke or
stroke/TIA Delayed: NOACs, >1, >2, days) systemic embolism without
>3, >4 days increasing major bleeding.
Marchis et Switzerland Prospective AF with 1362 (46.8) Early: NOACs ≦5 days Recurrent IS, ICH and Composite outcome 1.8%
al., 2022 observational acute 1188 (47.7); Delayed: NOACs > 5 days any-cause of mortality vs 1.5% (no difference)
ischemic 77 years (30 days)
stroke
Early or Delayed Anticoagulation in Patients with Atrial Fibrillation Upon Acute Ischemic Stroke: A Systematic Review and Meta-Analysis

AF indicates atrial fibrillation; AIS, acute ischemic stroke; ICH, intracranial hemorrhage; IS, ischemic stroke; NOAC, non-vitamin K antagonist oral anticoagulant;

77
TIA, transient ischemic attack.
 Early or Delayed Anticoagulation in Patients with Atrial Fibrillation Upon Acute Ischemic Stroke: A Systematic Review and Meta-Analysis

Figure 2. Forest plot of risk in primary composite outcome.

Figure 3. Forest plot of risk in recurrent ischemic stroke.

Forest plot demonstrated significantly lower risk
of recurrent ischemic stroke for early than delayed
initiation of anticoagulants (RR: 0.72; 95% CI:
0.57-0.91).
In 4 RCT studies with 3,134 patients (Figure
3), the forest plot demonstrated significantly lower
risk of recurrent ischemic stroke for early initiation
of anticoagulants than delayed administration
(RR: 0.73; 95% CI: 0.55-0.99). The heterogeneity
was low with I2 of 0% (P = 0.79). When focusing

78
 Early or Delayed Anticoagulation in Patients with Atrial Fibrillation Upon Acute Ischemic Stroke: A Systematic Review and Meta-Analysis
on the two large high-quality RCTs,13, 14 the early
treatment group (n = 1,434) showed significant
decreases in the risk of recurrent ischemic stroke
(RR: 0.62; 95% CI: 0.39-0.98) than delayed
treatment group (n = 1,429) and there was low
2
heterogeneity with I of 0% (P = 0.69).
In 6 eligible observational studies with 7,609
patients, the analysis showed non-significant
difference between two groups (RR: 0.78; 95% CI:
0.51-1.20) with moderate heterogeneity between
studies (I2 =47%; P = 0.09) (Figure 3).
Risk of intracranial hemorrhage
between early vs. delayed
initiation of OAC
The comparison between early vs. delayed
treatment of OAC for risk of ICH was shown
in Figure 4. The forest plot in 3 RCTs and 7
observational studies (n = 10,002) revealed no
significant difference in risk of ICH between early
(n = 4,939) and delayed (n = 5,063) administration
Figure 4. Forest plot of risk in intracranial hemorrhage.
of anticoagulants (RR: 0.91; 95% CI: 0.67-1.22).
The heterogeneity was low (I2 = 0%, P = 0.91).
In our respective subgroup analyses within
3 RCT studies with 2,246 patients or within 7
observational studies with 7,756 patients, there
were no significant differences in ICH risk between
early and delayed administration of anticoagulants
(RR: 1.08; 95% CI: 0.71-1.67 for RCTs; RR: 0.77;
95% CI: 0.51-1.16 for observational studies). The
heterogeneity was low between studies.
Discussion
This meta-analysis aims to assess whether
the early administration of NOACs or warfarin
in patients with AF during acute ischemic stroke
yields superior outcomes compared to the delayed
initiation of anticoagulants. Four RCTs and seven
observational studies were eligible for analyses,
and we demonstrated that the early treatment group
showed lower risk of composite outcome and less
79
 Early or Delayed Anticoagulation in Patients with Atrial Fibrillation Upon Acute Ischemic Stroke: A Systematic Review and Meta-Analysis
recurrent ischemic stroke compared to the delayed
treatment group without increasing the risk of
ICH. The results showed similar trend in subgroup
analyses within RCTs or within observational
studies, respectively. Overall, early administration
of oral anticoagulants in AF patients upon acute
ischemic stroke should be preferred over delayed
initiation of anticoagulation in general.
Early anticoagulation therapy decreases the
risk of recurrent embolism, but it also elevates the
risk of hemorrhagic transformation. Patients with
acute ischemic stroke associated with AF were
not included in pivotal RCTs comparing NOACs
and warfarin on effectiveness and safety, likely
due to concerns regarding the potential risk of
3
hemorrhagic transformation. Further observational
studies discussing about timing of anticoagulation
did not demonstrate consistent results. For
example, initiation of NOACs within 2 days after
acute ischemic stroke is associated with relative
high rate (5%) of hemorrhagic transformation. 22
On the other hand, the SAMURAI-NVAF study
showed that after initiation of NOACs, no ICH was
23
observed within 4 days after stroke. In addition,
the recommendation of various guidelines was
primarily based on expert consensus to initiate
anticoagulation after acute ischemic stroke. The
Canadian Heart and Stroke Foundation, European
Heart Rhythm Association, and TSS suggest to
follow the ‘1-3-6-12’ rule, according to different
9, 24, 25
stroke severity. The AHA/ASA recommended
to administer NOACs to patients with AF who
have experienced an acute ischemic stroke between
8
4 and 14 days after the event. The results of
our meta-analysis support that early initiation of
anticoagulation prevents more composite outcome
and recurrent ischemic stroke without increasing
risk of ICH, although the exact timing and strategy
differed significantly cross studies.
80
Until now, there are two large-scale high-
quality RCTs investigating early vs. delayed use
of NOAC after AF-related stroke. The TIMING
(Timing of oral anticoagulant therapy in acute
ischemic stroke with atrial fibrillation) clinical trial
is a noninferiority open-labeled RCT with subject
number of 450 in early anticoagulation group (≤4
days) and 438 in delayed anticoagulation group
(5-10 days). The study demonstrated that early
initiation of anticoagulants was noninferior to
delayed start of NOAC after acute ischemic stroke
with nonsignificant lower rates of ischemic stroke
and death. Notably, there was no ICH event in both
groups.13 The ELAN (Early versus Late initiation
of DOAC in post-ischemic stroke patients with
Atrial fibrillation) trial is a randomized controlled
open-label study with subject number of 1006 in
early anticoagulation group (≤2 days for minor and
moderate stroke and 6-7 days for major stroke)
and 1007 in delayed anticoagulation group (3-4
days for minor stroke; 6-7 days for moderate
stroke; 12-14 days for major stroke). The study
reported a lower rate of composite poor outcome
in early than later anticoagulation groups (1.18%
difference) with only 2 symptomatic ICH occurred
in each group (0.2%). 14 Our meta-analysis
focusing on these two RCTs demonstrated that
early anticoagulation with NOACs showed a trend
toward lower risk to develop events of composite
outcome than late administration of NOACs, and
therefore, supported a future direction of early
initiation of anticoagulation for these patients. Two
additional RCTs are still undergoing including
OPTIMAS (Optimal Timing of Anticoagulation
after Ischemic Stroke) and START (Optimal delay
time to initiate anticoagulation after ischemic
stroke in atrial fibrillation) trials. The final results
of these two important clinical trials are highly
anticipated.
 Early or Delayed Anticoagulation in Patients with Atrial Fibrillation Upon Acute Ischemic Stroke: A Systematic Review and Meta-Analysis
Our study has several limitations: (1) The
variability in study designs and the timing of
anticoagulation across different studies poses a
challenge to the direct clinical application of the
concept advocating early anticoagulant use; (2)
In both RCTs and observational studies, certain
investigations compared outcomes between
NOACs and warfarin. It is crucial to recognize
that the results may be influenced by the choice
of anticoagulant type rather than being solely
attributable to the timing of anticoagulant
administration; (3) All of the 4 RCTs were not
double blinded with two of them being open-
label trials and two of them being single masking
studies, leading to a potential risk of biased
reporting for clinical events; (4) There is racial
deviation for the RCTs that the trial population
consisted primarily of participants from European
centers, where there was a high proportion of
White individuals; (5) The majority of RCTs and
observational studies focused on patients with
mild to moderate stroke severity, a group generally
perceived to carry a lower risk of ICH when early
oral anticoagulation is initiated. Therefore, the
findings may not apply to individuals with severe
stroke or with large infarct size. Future large RCTs
are needed with a special target in this subgroup.
In conclusion, for patients with AF-
related acute ischemic stroke, our meta-analysis
demonstrated that early initiation of anticoagulation
is superior than delayed administration for reducing
composite outcome and recurrent ischemic stroke
without posing additional risk on ICH. Further
large RCTs are still mandatory not only to confirm
the benefits of early anticoagulation in these
patients, but to delineate the exact timing strategy
of drug initiation with or without stratifying stroke
severity for practical clinical application.
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 Early or Delayed Anticoagulation in Patients with Atrial Fibrillation Upon Acute Ischemic Stroke: A Systematic Review and Meta-Analysis

心房顫動患者急性缺血性中風後的早期或延遲抗凝
治療：系統性回顧與統合分析

羅彥伶 1、 蔡欣熹 1, 2、蔡力凱 1, 3

1
台大醫院 神經部暨腦中風中心
2
台大醫院北護分院 神經科
3
新竹台大分院 神經部

摘 要
背景：針對心房顫動患者，何時在急性缺血性中風後開始使用warfarin或新型口服抗凝血劑
(NOAC)，至今最佳策略仍然未知。過去臨床試驗或觀察性研究探討了早期使用NOAC的利弊，但
這些研究的方法學和結論不盡相同，需要統合分析以提供整體的療效比較。
研究方法：由Pubmed及Scopus電子資料庫平台收尋相關醫學文獻，共可得到204篇文章。依照
設定的納入及排除條件後，共獲得4篇隨機的臨床試驗與7篇觀察性研究進行統合分析。我們嘗試比
較早期或延遲抗凝治療(warfarin或NOAC)之預後，包括複合性預後指標、再次復發的缺血性中風或
顱內出血的相關風險。
研究結果：於臨床試驗與觀察性研究之8,874名心房顫動患者，隨機效應模型的統合分析顯
示，早期給藥較晚期給藥顯著減少複合式預後指標(相對風險：0.75；95%信賴區間：0.58-0.96)。而
針對次級指標，於10,743名心房顫動患者，早期給藥較晚期給藥顯著減少復發性缺血性腦中風 (相
對風險：0.72；95%信賴區間：0.51-0.91)；而於10,002名心房顫動患者，早期給藥和晚期給藥之顱
內出血風險相似(相對風險：0.91；95%信賴區間：0.67-1.22)。若統合分析僅侷限於2個大型高品質
之NOAC隨機對照試驗，於2,901名心房顫動患者中，早期給藥較晚期給藥呈現複合式預後指標減少
的趨勢，但統計並不顯著(相對風險：0.75；95%信賴區間：0.54-1.04)。
研究結論：在心房顫動的急性缺血性腦中風患者，於中風後早期給予口服抗凝血劑比延後給予
藥物治療，可能可以減少整體的不良預後。其中早期給予抗凝血藥物似乎可降低復發性缺血性中風
的發生率，且無增加中風後出血發生的機會。

關鍵詞：心房顫動，早期使用，缺血性中風，顱內出血，抗凝血劑

通訊作者：蔡欣熹醫師，台大醫院神經部暨腦中風中心
E-mail: tsaihsinhsi@gmail.com

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