Keywords
atrial fibrillation - acute ischemic stroke - oral anticoagulants - timing - stroke
recurrence
Introduction
Stroke is a leading cause of mortality and disability, resulting in substantial economic
costs in terms of poststroke care.[1] Cardioembolic strokes, most frequently caused by atrial fibrillation (AF),[2] are found to be related to worse outcomes compared with other non-AF-related strokes.
Lifelong use of oral anticoagulants (OACs) has been recommended for secondary stroke
prevention.[3]
[4] However, the optimal timing to resume OAC in AF patients with acute ischemic stroke
(AIS) remains a clinical challenge. Early non-vitamin K antagonist OACs (NOACs) within
2 days of AIS had been shown to be associated with a 5% rate of hemorrhagic transformation,[5] whereas a delayed initiation may leave the patients at an increased risk of recurrent
ischemic stroke. The 2018 European Heart Rhythm Association practical guide proposed
a “1–3–6–12 days rule” to resume OAC after an AIS in patients with AF,[4]
[6] based on expert consensus opinion without supporting evidence from large-scale randomized
controlled trials (RCTs). Recently, one meta-analysis of individual-level data from
seven prospective observational studies, including CROMIS-2,[7] RAF,[8] RAF-NOACs,[9] SAMURAI,[10] NOACISP,[11] Erlangen,[12] and Verona[13] registry, suggested that that early NOAC treatment after AIS, when compared with
vitamin K antagonist (VKA), was associated with a reduced risk of intracranial hemorrhage
(ICH).[14] Interestingly, Mizoguchi and colleagues compared the early (≤3 days) with the delayed
(≥4 days) initiation of NOACs after AIS or transient ischemic attack (TIA) in the
SAMURAI study and did not observe a difference in risks of stroke, major bleeding,
and death between the groups.[15] The study by Mizoguchi and coauthors, however, did not address the potential immortal-time
bias because patients who initiated NOACs in the delayed period, by definition, had
to be alive and free of ischemic stroke in the early period (and thus to be “immortal”
to outcomes of interest.)
Four ongoing RCTs, including ELAN (NCT03148457, Switzerland), OPTIMAS (EudraCT, 2018003859–38,
United Kingdom), TIMING (NCT02961348, Sweden), and START (NCT03021928, United States),
are to determine the optimal time for initiating OACs after AIS. However, these RCTs
only compare the early and delayed initiation of NOACs with fixed intervals, without
stratified randomization based on prespecified AIS severity, except ELAN stratifies
patients based on the size of the infarction. Moreover, these RCTs fail to investigate
the comparative effectiveness and safety of VKA in patients with AIS secondary to
AF.
The present study aimed to examine the benefit and risk of early and delayed use of
OACs, including NOACs and VKAs, in AF patients hospitalized for AIS. Immortal-time
bias is a challenging issue in comparing different strategies of treatment initiation
in observational studies, and we constructed a sequence of stroke severity-specific
cohorts with propensity score (PS) matching to reduce immortal-time bias and confounding
bias. The study results could provide real-world evidence of the optimal timing to
initiate OACs after an AIS event among patients with AF.
Methods
Taiwan National Health Insurance Research Databases
Taiwan initiated its single-payer, universal National Health Insurance program in
March 1995. Enrolment is mandatory. As of 2020, membership consisted of approximately
23,622,000 individuals (99·9% of Taiwan's population). The National Health Insurance
Research Database (NHIRD) captures all medical claims, including disease diagnoses,
procedures, and prescription fills in the records of inpatient, outpatient, and emergency
visits since 2000 for research purposes. The consistency, reliability, and disease
diagnostic accuracy of the NHIRD for research in cardiovascular, bleeding, and mortality
outcomes among patients with AF and/or AIS have been validated.[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23] The Institutional Review Board of the National Yang-Ming University, Taiwan, approved
this research study (YM104104E).
Study Population
The base cohort included 268,715 patients who presented a new AIS (“index stroke event”)
from January 1, 2012 to December 31, 2016, who did not have a diagnosis of hemorrhagic
stroke or TIA on the admission day, and who did not have any inpatient diagnosis of
ischemic stroke within 5 years before the index stroke event ([Fig. 1]). Using algorithms validated in the NHIRD, AIS was validated by the noncontrast
computed tomography (CT) or magnetic resonance imaging (MRI),[21] and AF was defined as having at least one inpatient or outpatient record of the
International Classification of Diseases (ICD)-9 or ICD-10 diagnosis code for AF as
the primary diagnosis, or having at least two records of AF diagnosis as the secondary
diagnosis within 5 years before the index stroke event[23]
[24] ([Supplementary Table S1], available in the online version). The final study population consisted of 12,307
AF patients with a new AIS, after excluding patients who lacked AF diagnosis in 2007
to 2011 (n = 252,607), were of unknown sex (n = 13), died on admission (n = 16), or had an ICH diagnosis on admission (n = 3,772).
Fig. 1 Flowchart of patient selection. AIS, acute ischemic stroke.
Severity of Acute Ischemic Stroke
We calculated a validated stroke severity index (SSI) to categorize the index stroke
event into mild (SSI ≤ 5), moderate (5 < SSI ≤ 12), and severe (SSI >12) stroke.[25]
[26]
[27] Stroke severity assessed by the National Institutes of Health Stroke Scale (NIHSS)
cannot be captured in the administrative claims data, and SSI was closely correlated
with NIHSS[27] and performed well in 30-day and 1-year mortality prediction in validation studies.[26] SSI calculation was based on the number of the following tests on admission: airway
suctioning, bacterial sensitivity test, general ward stay, intensive care unit stay,
nasogastric intubation, osmotherapy (mannitol or glycerol), and urinary catheterization.[27]
Guideline-Recommended OAC Use in AF Patients Hospitalized for Stroke
Guidelines recommend initiation of OACs, including NOACs or warfarin, on the 4th day
of admission for a minor AIS, 7th day for a moderate AIS, and 13th day for a severe
AIS.[4]
[6] Depending on the stroke severity, “early use” referred to initiation of OACs within
3 (minor AIS), 6 (moderate AIS), or 12 days (severe AIS) of admission; “delayed use”
referred to initiation of OACs between the guideline-recommended initiation day and
the 30th day of admission. On a specific day, the exposed group included patients
who initiated OACs and the unexposed group included patients who did not initiate
OACs. Information of NOAC or warfarin initiation was based on prescriptions in inpatient
and outpatient settings. Within 30 days of admission, patients who had prescriptions
of NOAC only or VKA only were categorized into the “NOAC group” or the “VKA group,”
respectively, and patients who had prescriptions of both NOAC and VKA were categorized
into the “both group.”
Composite Outcome of Effectiveness and Safety
The primary outcome was the first occurrence of a composite outcome of an effectiveness
or a safety event. Effectiveness outcomes included ischemic stroke, myocardial infarction
(MI), TIA, systemic embolism, venous thromboembolism (VTE), and cardiovascular death.
Safety outcomes included ICH, gastrointestinal (GI) bleeding, and hematuria. These
outcome events were identified using ICD-9 or ICD-10 diagnosis codes in inpatient
records based on validated algorithms in the NHIRD[16]
[18]
[19]
[20]
[21]
[22]
[23]
[28] ([Supplementary Table S1], available in the online version).
Immortal-Time Bias and the Sequence of Cohorts with PS-Matching on Each Day of OAC
Initiation
Immortal time refers to a period of cohort follow-up when study subjects cannot have
outcome(s) because of exposure definition. For example, patients who initiated an
OAC on the sixth day of admission had to be alive and cannot develop any outcome from
the first to the sixth day. Additionally, patients may initiate OACs on a specific
day based on physicians' decisions, patients' clinical status, and possibly guideline
suggestions.[6] Consequently, the early and delayed use groups likely have different baseline risks
of outcomes, and a direct comparison between the two groups could introduce immortal-time
bias and confounding bias.[29]
[30] To reduce these biases, we constructed a sequence of PS-matched cohorts of OAC users
and nonusers, creating one cohort on each day of OAC initiation for 30 days since
admission ([Fig. 2]).[30] The day of OAC initiation was defined as the index date for each cohort. Across
the three categories of stroke severity and the 30 possible days of OAC initiation,
we constructed 90 PS-matched cohorts nested within the study population (n = 12,307) for each of the composite outcome, effectiveness outcome, and safety outcome.
The analytic sample of AF patients eligible for PS-matching included 10,956 patients
for the composite outcomes, 11,529 patients for the effectiveness outcomes, and 11,709
patients for the safety outcomes ([Fig. 1]).
Fig. 2 A sequence of propensity-score matched cohorts on each day of OAC initiation from
the first to the 30th day of admission, using AF patients with mild AIS as an example.
AF, atrial fibrillation; AIS, acute ischemic stroke; OAC, oral anticoagulant.
Follow-up for each PS-matched cohort started from the cohort index date until the
first occurrence of a composite outcome event, noncardiovascular death, loss to follow-up,
initiation of OACs in an unexposed group, or December 31, 2017.
Statistical Analyses
On each of the cohort index dates, we calculated PS using a logistic regression model
that included age, sex, use of medication (antihypertensive drugs, antidiabetic drugs,
lipid-lowering drugs, OACs, antiplatelets, nonsteroid anti-inflammatory drugs), and
medical history of liver disease, peptic ulcer, hypertension, dyslipidemia, ischemic
heart disease, ICH, TIA, alcohol intoxication, GI bleeding, hematuria, VTE, systemic
embolism, congestive heart failure (CHF), MI, peripheral vascular disease (PVD), cerebrovascular
accident, diabetes mellitus, and chronic kidney disease (CKD). We 1:1 matched OAC
users to nonusers using the greedy nearest-neighbor technique within a specified caliper
width of 0·25 of the standard deviation of the logit of the PS.[31] A nonuser was allowed to be matched to multiple OAC users who initiated OACs on
different days. Nonusers could later initiate OACs and become OAC users.
For each level of AIS severity, we pooled all PS-matched cohorts into one analytic
sample.[32] Using nonusers as the reference, we performed Cox proportional-hazards models to
estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes in the
early use and separately in the delayed use. We stratified Cox models on the index
date and adjusted for the PS-matching variables. We used a robust variance estimate
to account for within-person correlation.[32]
We used the cumulative incidence function[33] to calculate cumulative incidence to account for possible competing risks.[34] Categorical variables were expressed as the number (percentage) and assessed using
the Chi-square (χ2) or Fisher's exact test.
Mixed Treatment Comparison
We indirectly compared the risk of outcomes in the early with the delayed use groups
using a random-effects model.[35] The indirect comparisons were based on the assumptions of cohort independence and
consistency between direct and indirect comparisons. We applied the results comparing
the exposed with the unexposed group as direct evidence, and extrapolated the indirect
comparison from the direct evidence.
Net Clinical Benefit Analysis
We performed a net clinical benefit (NCB) analysis, proposed by Singer et al[36], to examine the risk and benefit profile of early or delayed OAC use, compared with
the no use group. The NCB was calculated as: (rate of effectiveness outcome in the
no use group – rate of effectiveness outcome in the early [or delayed] use group) − weighting
factor × (rate of safety outcome in the early [or delayed] use group – rate of safety
outcome in the no use group). The 95% CIs were calculated from rate differences and
standard errors estimates using Poisson regression. The weighting factor reflects
the relative impact of a safety outcome while receiving an early or a delayed OAC,
as opposed to experiencing an effectiveness outcome while not using OACs. We selected
three weighting factors (1.5, 2.0, and 3.0) based on publications of the risk and
benefit of warfarin use in AF patients.[36]
[37]
Results
Of the 10,956 patients with AF in the composite outcome analysis ([Supplementary Table S2], available in the online version), 41·2% (n = 4,513) had a mild stroke, 23·6% (n = 2,582) had a moderate stroke, and 35·2% (n = 3,861) had a severe stroke. Among patients with AF, the proportion of guideline-recommended
use of OACs decreased with an increasing stroke severity (early use: 29·0, 26·8, and
21·8%; delayed use: 25·9, 22·2, and 14·5% in mild, moderate, and severe stroke, respectively).
Conversely, the proportion of patients with no OAC use increased (45·1, 51·0, and
63·7% in mild, moderate, and severe stroke, respectively).
Across the stroke severity, AF patients who did not initiate OACs after an AIS tended
to be older and have more comorbidities than those who did ([Table 1], [Supplementary Tables S3–S13], available in the online version). For example, peptic ulcers, hypertension, ICH,
GI bleeding, CHF, MI, PVD, diabetes, and CKD were more common in AF patients with
mild stroke in the no use group than those in the early or delayed OAC use group (all
p-values before PS-matching: <0·05; [Table 1]). Patients in the no use group were more likely to use antiplatelet therapy and
less likely to use OAC at baseline than those in the OAC use groups (p-values before PS-matching: <0·05; [Table 1]). After PS-matching, differences between the OAC use and no use groups disappeared.
Table 1
Baseline characteristics of AF patients with mild stroke before and after PS-matching
in the analytic sample for composite outcome
|
Unmatched cohort (n = 4,513)
|
PS-matched cohorts
|
|
Early use (n = 1,307)
|
Delayed use (n = 1,171)
|
No use (n = 2,035)
|
p-Value[a]
|
p-Value[b]
|
Early use (n = 1,307)
|
No use (n = 1,307)
|
p-Value
|
Delayed use (n = 1,171)
|
No use (n = 1,171)
|
p-Value
|
|
Gender
|
|
|
|
0·308
|
0·224
|
|
|
0·694
|
|
|
0·706
|
|
Female
|
597 (45·7)
|
488 (41·7)
|
893 (43·9)
|
|
|
597 (45·7)
|
587 (44·9)
|
|
488 (41·7)
|
497 (42·4)
|
|
|
Male
|
710 (54·3)
|
683 (58·3)
|
1,142 (56·1)
|
|
|
710 (54·3)
|
720 (55·1)
|
|
683 (58·3)
|
674 (57·6)
|
|
|
Age
|
|
|
|
<0·001
|
<0·001
|
|
|
<0·001
|
|
|
0·991
|
|
≥80
|
433 (33·1)
|
383 (32·7)
|
921 (45·3)
|
|
|
433 (33·1)
|
436 (33·4)
|
|
383 (32·7)
|
380 (32·5)
|
|
|
70–80
|
470 (36·0)
|
426 (36·4)
|
654 (32·1)
|
|
|
470 (36·0)
|
482 (36·9)
|
|
426 (36·4)
|
428 (36·5)
|
|
|
< 70
|
404 (30·9)
|
362 (30·9)
|
460 (22·6)
|
|
|
404 (30·9)
|
389 (29·8)
|
|
362 (30·9)
|
363 (31·0)
|
|
|
Medication use
|
|
Antihypertensive
|
1,158 (88·6)
|
993 (84·8)
|
1767 (86·8)
|
0·131
|
0·109
|
1,158 (88·6)
|
1,146 (87·7)
|
0·468
|
993 (84·8)
|
996 (85·1)
|
0·862
|
|
Antidiabetic
|
366 (28·0)
|
298 (25·5)
|
601 (29·5)
|
0·341
|
0·013
|
366 (28·0)
|
376 (28·8)
|
0·664
|
298 (25·5)
|
300 (25·6)
|
0·924
|
|
Lipid-lowering agents
|
306 (23·4)
|
277 (23·6)
|
425 (20·9)
|
0·084
|
0·067
|
306 (23·4)
|
300 (22·9)
|
0·780
|
277 (23·6)
|
274 (23·4)
|
0·883
|
|
Anticoagulant
|
622 (47·6)
|
271 (23·1)
|
237 (11·6)
|
<0·001
|
<0·001
|
622 (47·6)
|
625 (47·8)
|
0·906
|
271 (23·1)
|
267 (22·8)
|
0·844
|
|
Antiplatelet
|
601 (46·0)
|
622 (53·1)
|
1197 (58·8)
|
<0·001
|
0·002
|
601 (46·0)
|
620 (47·4)
|
0·456
|
622 (53·1)
|
587 (50·1)
|
0·147
|
|
NSAIDs
|
1,307 (100)
|
1,171 (100)
|
2,032 (99·8)
|
1
|
1
|
1,307 (100)
|
1,307 (100)
|
1
|
1,171 (100)
|
1,171 (100)
|
1
|
|
Comorbidities
|
|
Liver disease
|
179 (13·7)
|
193 (16·5)
|
306 (15·0)
|
0·283
|
0·277
|
179 (13·7)
|
170 (13·0)
|
0·604
|
193 (16·5)
|
174 (14·9)
|
0·280
|
|
Peptic ulcer disease
|
353 (27·0)
|
344 (29·4)
|
706 (34·7)
|
<0·001
|
0·002
|
353 (27·0)
|
357 (27·3)
|
0·860
|
344 (29·4)
|
314 (26·8)
|
0·167
|
|
Hypertension
|
1028 (78·6)
|
924 (78·9)
|
1694 (83·2)
|
<0·001
|
0·002
|
1,028 (78·6)
|
1,054 (80·6)
|
0·206
|
924 (78·9)
|
931 (79·5)
|
0·721
|
|
Dyslipidemia
|
454 (34·7)
|
414 (35·3)
|
707 (34·7)
|
0·997
|
0·726
|
454 (34·7)
|
459 (35·1)
|
0·837
|
414 (35·3)
|
392 (33·5)
|
0·338
|
|
IHD
|
615 (47·1)
|
547 (46·7)
|
1021 (50·2)
|
0·078
|
0·059
|
615 (47·0)
|
626 (47·9)
|
0·666
|
547 (46·7)
|
539 (46·0)
|
0·740
|
|
ICH
|
26 (2·0)
|
20 (1·7)
|
63 (3·1)
|
0·052
|
0·017
|
26 (2·0)
|
28 (2·1)
|
0·783
|
20 (1·7)
|
16 (1·4)
|
0·501
|
|
TIA
|
94 (7·2)
|
76 (6·5)
|
154 (7·6)
|
0·686
|
0·255
|
94 (7·2)
|
115 (8·8)
|
0·129
|
76 (6·5)
|
69 (5·9)
|
0·548
|
|
Alcohol intoxication
|
10 (0·8)
|
10 (0·8)
|
24 (1·2)
|
0·244
|
0·386
|
10 (0·8)
|
12 (0·9)
|
0·668
|
10 (0·8)
|
9 (0·8)
|
0·817
|
|
GI bleeding
|
125 (9·6)
|
113 (9·6)
|
277 (13·6)
|
<0·001
|
0·001
|
125 (9·6)
|
131 (10·0)
|
0·693
|
113 (9·6)
|
104 (8·9)
|
0·521
|
|
Hematuria
|
65 (5·0)
|
57 (4·9)
|
94 (4·6)
|
0·638
|
0·749
|
65 (5·0)
|
68 (5·2)
|
0·789
|
57 (4·9)
|
47 (4·0)
|
0·316
|
|
VTE
|
27 (2·1)
|
18 (1·5)
|
31 (1·5)
|
0·241
|
0·975
|
27 (2·1)
|
33 (2·5)
|
0·433
|
18 (1·5)
|
18 (1·5)
|
1
|
|
Systemic embolism
|
29 (2·2)
|
28 (2·4)
|
63 (3·1)
|
0·130
|
0·247
|
29 (2·2)
|
34 (2·6)
|
0·523
|
28 (2·4)
|
22 (1·89)
|
0·391
|
|
CHF
|
602 (46·1)
|
448 (38·3)
|
907 (44·6)
|
0·398
|
<0·001
|
602 (46·1)
|
576 (44·1)
|
0·306
|
448 (38·3)
|
431 (36·8)
|
0·468
|
|
Myocardial infarction
|
90 (6·9)
|
68 (5·8)
|
193 (9·5)
|
0·008
|
<0·001
|
90 (6·9)
|
77 (5·9)
|
0·298
|
68 (5·8)
|
63 (5·4)
|
0·653
|
|
PVD
|
107 (8·2)
|
76 (6·5)
|
200 (9·8)
|
0·108
|
0·001
|
107 (8·2)
|
95 (7·3)
|
0·379
|
76 (6·5)
|
60 (5·1)
|
0·157
|
|
CVA
|
610 (46·7)
|
558 (47·6)
|
953 (46·8)
|
0·928
|
0·653
|
610 (46·7)
|
590 (45·1)
|
0·432
|
558 (47·6)
|
550 (47·0)
|
0·740
|
|
Diabetes mellitus
|
458 (35·0)
|
390 (33·3)
|
796 (39·1)
|
0·017
|
0·001
|
458 (35·0)
|
463 (35·4)
|
0·837
|
390 (33·3)
|
376 (32·1)
|
0·537
|
|
CKD
|
361 (27·6)
|
300 (25·6)
|
678 (33·3)
|
<0·001
|
<0·001
|
361 (27·6)
|
370 (28·3)
|
0·694
|
300 (25·6)
|
293 (25·0)
|
0·739
|
|
Secondary prevention with OAC use
|
|
NOAC only
|
354 (27·1)
|
666 (56·9)
|
0
|
|
|
354 (27·1)
|
0
|
|
666 (56·9)
|
0
|
|
|
Warfarin only
|
811 (62·0)
|
449 (38·3)
|
0
|
|
|
811 (62·1)
|
0
|
|
449 (38·3)
|
0
|
|
|
Both
|
142 (10·8)
|
56 (4·8)
|
0
|
|
|
142 (10·9)
|
0
|
|
56 (4·8)
|
0
|
|
|
Antiplatelet[c]
|
n/a
|
n/a
|
n/a
|
|
|
829 (63·4)
|
829 (63·4)
|
1
|
987 (84·3)
|
979 (83·6)
|
0·652
|
Abbreviations: AF, atrial fibrillation; AIS, acute ischemic stroke; CHF, congestive
heart failure; CKD, chronic kidney disease; CVA, cerebrovascular accident; GI, gastrointestinal;
ICH, intracranial hemorrhage; IHD, ischemic heart disease; NOAC, non-vitamin K antagonist
oral anticoagulant; NSAIDs, nonsteroidal anti-inflammatory drugs; OACs, oral anticoagulants;
PS-matched, propensity score-matched; PVD, peripheral vascular disease; TIA, transient
ischemic attack; VTE, venous thromboembolism.
Note: Data are shown in n (%). Statistically significant p-values are denoted in bold.
a
p-Value: comparing early use versus no use.
b
p-Value: comparing delayed use versus no use.
c Antiplatelet use from the day of AIS admission to the index date (i.e., the day of
OAC initiation or matching).
As the stroke severity increased from mild to severe ([Supplementary Table S14], available in the online version), the incidence of composite outcome increased
(444·5 to 928·3 cases per 1,000 person-years), as did the incidence of effectiveness
outcome (292·1 to 654·7 cases per 1,000 person-years). The incidence of safety outcome
did not vary substantially (149·5 to 196·4 cases per 1,000 person-years).
Use of OACs versus No Use and the Risk of Outcomes
AF Patients with Mild or Moderate Stroke
When compared with no OAC use, the early or delayed use was associated with a decreased
risk of composite outcome with HR ranging from 0·73 (95% CI: 0·62–0·85) to 0·82 (95%
CI: 0·67–1·00). The OAC use was not associated with an increased risk of safety outcomes
([Table 2]).
Table 2
Hazard ratio and 95% confidence interval for the composite outcome, effectiveness
outcome, and safety outcome, in the early OAC use group and in the delayed OAC use
group[a]
|
Stroke severity
|
Mild
|
Moderate
|
Severe
|
|
OAC use
|
Early vs. no use
|
Delayed vs. no use
|
Early vs. no use
|
Delayed vs. no use
|
Early vs. no use
|
Delayed vs. no use
|
|
Composite outcome
|
|
0·75 (0·65, 0·87)
|
0·73 (0·62, 0·85)
|
0·73 (0·61, 0·88)
|
0·82 (0·67, 1·00)
|
0·79 (0·68, 0·92)
|
0·89 (0·73, 1·08)
|
|
Stratified by:
|
|
NOAC
|
0·64 (0·47, 0·85)
|
0·61 (0·49, 0·76)
|
0·59 (0·38, 0·93)
|
0·73 (0·55, 0·97)
|
0·77 (0·51, 1·17)
|
1·10 (0·84, 1·45)
|
|
Warfarin
|
0·89 (0·74, 1·06)
|
0·88 (0·68, 1·14)
|
0·79 (0·63, 1·00)
|
0·76 (0·55, 1·06)
|
0·86 (0·72, 1·03)
|
0·61 (0·45, 0·82)
|
|
Effectiveness outcome
|
|
0·83 (0·70, 0·98)
|
0·69 (0·58, 0·83)
|
0·88 (0·72, 1·07)
|
0·84 (0·68, 1·03)
|
0·82 (0·70, 0·95)
|
0·76 (0·63, 0·92)
|
|
Stratified by:
|
|
NOAC
|
0·78 (0·56, 1·07)
|
0·52 (0·40, 0·68)
|
0·93 (0·59, 1·46)
|
0·82 (0·63, 1·08)
|
0·58 (0·39, 0·86)
|
1·02 (0·78, 1·32)
|
|
Warfarin
|
0·86 (0·69, 1·06)
|
0·99 (0·75, 1·30)
|
0·95 (0·75, 1·20)
|
0·80 (0·56, 1·14)
|
0·98 (0·82, 1·18)
|
0·52 (0·39, 0·71)
|
|
Safety outcome
|
|
0·96 (0·76, 1·22)
|
0·75 (0·61, 0·93)
|
1·08 (0·80, 1·46)
|
0·94 (0·69, 1·28)
|
1·67 (1·30, 2·13)
|
1·16 (0·88, 1·53)
|
|
Stratified by:
|
|
NOAC
|
1·00 (0·58, 1·71)
|
0·77 (0·58, 1·03)
|
1·13 (0·61, 2·10)
|
0·81 (0·51, 1·28)
|
2·10 (1·13, 3·92)
|
1·18 (0·78, 1·78)
|
|
Warfarin
|
0·95 (0·71, 1·28)
|
0·73 (0·52, 1·02)
|
1·07 (0·73, 1·57)
|
1·11 (0·68, 1·80)
|
1·76 (1·29, 2·39)
|
1·05 (0·69, 1·59)
|
Abbreviations: AF, atrial fibrillation; NOAC, non-vitamin K antagonist oral anticoagulant;
OACs, oral anticoagulants.
Note: Statistically significant values are denoted in bold.
a A sequence of PS-matched cohorts for each of the three outcomes was constructed on
each day from the first to the 30th day of admission. Data of PS-matched cohorts were
pooled together for analyses.
AF Patients with Severe Stroke
Early use of OACs, compared with no use, was associated with a 0.79-fold (95% CI:
0.68–0.92) risk of composite outcome, 0.82-fold (95% CI: 0.70–0.95) risk of effectiveness
outcome, and 1.67-fold (95% CI: 1.30–2.13) risk of safety outcomes. In NOAC- and warfarin-specific
analyses, early use of NOAC was associated with a 0·58-fold (95% CI: 0·39–0·86) risk
of effectiveness outcome and a 2.10-fold (95% CI: 1·13–3·92) risk of safety outcome.
On the contrary, delayed use of warfarin was associated with a 0·52-fold (95% CI:
0.35–0.71) risk of effectiveness outcomes and was not associated with an increased
risk of safety outcomes ([Table 2]).
Early versus Delayed Use of OACs and the Risk of Outcomes
Across the stroke severity level, the risk of composite or effectiveness outcomes
did not significantly differ between the early use and the delayed use groups ([Table 3]). However, a trend of an increased risk of safety outcomes associated with the early
use of OACs was observed, particularly in patients with severe stroke (HR: 1·44, 95%
CI: 0·99–2·09, delayed use as reference). In AF patients with severe stroke, the risk
of effectiveness outcome was lower in the early use than the delayed use of NOAC (HR:
0·57, 95% CI: 0·35–0·91); the opposite was observed in comparing the early use with
the delayed use of warfarin (HR: 1.88, 95% CI: 1.33–2.68).
Table 3
Hazard ratio and 95% confidence intervals for the composite outcome, effectiveness
outcome, and safety outcome, comparing the early use with the delayed use of OACs
in mixed treatment comparison[a]
|
Stroke severity
|
Mild
|
Moderate
|
Severe
|
|
Composite outcome
|
1·03 (0·83, 1·27)
|
0·89 (0·68, 1·17)
|
0·89 (0·69, 1·14)
|
|
Stratified by:
|
|
NOAC
|
1·05 (0·73, 1·52)
|
0·81 (0·48, 1·37)
|
0·70 (0·43, 1·15)
|
|
Warfarin
|
1·01 (0·74, 1·39)
|
1·04 (0·70, 1·55)
|
1·41 (0·99, 2·00)
|
|
Effectiveness outcome
|
1·20 (0·94, 1·54)
|
1·05 (0·79, 1·40)
|
1·08 (0·85, 1·38)
|
|
Stratified by:
|
|
NOAC
|
1·50 (0·99, 2·28)
|
1·13 (0·67, 1·92)
|
0·57 (0·35, 0·91)
|
|
Warfarin
|
0·87 (0·61, 1·23)
|
1·19 (0·78, 1·82)
|
1·88 (1·33, 2·68)
|
|
Safety outcome
|
1·28 (0·93, 1·76)
|
1·15 (0·75, 1·77)
|
1·44 (0·99, 2·09)
|
|
Stratified by:
|
|
NOAC
|
1·30 (0·70, 2·40)
|
1·40 (0·65, 3·01)
|
1·78 (0·84, 3·75)
|
|
Warfarin
|
1·30 (0·83, 2·04)
|
0·96 (0·52, 1·79)
|
1·68 (0·998, 2·82)
|
Abbreviations: AF, atrial fibrillation; NOAC, non-vitamin K antagonist oral anticoagulant;
OACs, oral anticoagulants.
Note: Statistically significant values are denoted in bold.
a Reference group for all mixed treatment comparison was the delayed OAC use.
Net Clinical Benefit for OAC Use
In patients with mild or moderate stroke, early or delayed use of OACs was associated
with a statistically significant NCB, as opposed to no OAC use ([Table 4]). In patients with severe stroke, use of OACs, compared with no use, was also associated
with a NCB although the benefit did not reach statistical significance in the delayed
use group.
Table 4
Net clinical benefit for the early use and for the delayed use of OACs compared with
no use
|
Effectiveness outcome
|
Safety outcome
|
Net clinical benefit (95% CI)[a]
|
|
n
|
Person-year (p-yr)
|
Incidence (1,000 p-yr)
|
n
|
Person-year
|
Incidence (1,000 p-yr)
|
Weighting factor[b]
|
|
1.5
|
2.0
|
3.0
|
|
Mild stroke
|
|
Early use
|
570
|
2,009.0
|
283.7
|
349
|
2,493.6
|
140.0
|
0.16 (0.09, 0.23)
|
0.17 (0.08, 0.25)
|
0.19 (0.08, 0.30)
|
|
No use
|
250
|
600.6
|
416.3
|
119
|
753.3
|
158.0
|
Ref
|
Ref
|
Ref
|
|
Delayed use
|
447
|
1,813.9
|
246.4
|
330
|
2,245.7
|
146.9
|
0.10 (0.04, 0.15)
|
0.11 (0.04, 0.17)
|
0.13 (0.04, 0.22)
|
|
No use
|
352
|
1,119.6
|
314.4
|
226
|
1,356.6
|
166.6
|
Ref
|
Ref
|
Ref
|
|
Moderate stroke
|
|
Early use
|
356
|
908.6
|
391.8
|
190
|
1,152.0
|
164.9
|
0.31 (0.18, 0.45)
|
0.34 (0.19, 0.49)
|
0.38 (0.19, 0.58)
|
|
No use
|
179
|
280.6
|
638.0
|
68
|
323.8
|
210.0
|
Ref
|
Ref
|
Ref
|
|
Delayed use
|
269
|
814.2
|
330.4
|
170
|
1,021.3
|
166.4
|
0.20 (0.09, 0.30)
|
0.22 (0.10, 0.34)
|
0.27 (0.10, 0.44)
|
|
No use
|
203
|
448.1
|
453.0
|
96
|
445.7
|
215.4
|
Ref
|
Ref
|
Ref
|
|
Severe stroke
|
|
Early use
|
487
|
742.9
|
655.6
|
219
|
1,032.3
|
212.1
|
0.25 (0.11, 0.38)
|
0.25 (0.09, 0.40)
|
0.25 (0.05, 0.44)
|
|
No use
|
330
|
365.1
|
903.9
|
95
|
450.1
|
211.1
|
Ref
|
Ref
|
Ref
|
|
Delayed use
|
321
|
597.8
|
537.0
|
141
|
853.6
|
165.2
|
0.12 (−0.01, 0.26)
|
0.14 (−0.01, 0.29)
|
0.18 (−0.002, 0.37)
|
|
No use
|
249
|
412.7
|
603.3
|
99
|
485.0
|
204.1
|
Ref
|
Ref
|
Ref
|
Abbreviations: CI, confidence interval; OAC, oral anticoagulant.
a Net clinical benefit was calculated as: (rate of effectiveness outcome in the no
use group – rate of effectiveness outcome in the early [or delayed] use group − weighting
factor × (rate of safety outcome in the early [or delayed] use group – rate of safety
outcome in the no use group), originally proposed by Singer et al.[36]
b The weighting factor reflects the relative impact, in terms of death and disability,
of a safety outcome while receiving an early or a delayed OAC versus experiencing
an effectiveness outcome while not using OACs. The weighting factors were based on
those in the publications.[36]
[37]
Discussion
This study provided the first evidence of a large-scale population and evaluated the
effects of early or delayed OAC initiation in a population with AF after AIS by PS-matched
cohort on each day since admission, stratified by stroke severity, to overcome immortal-time
biases by emulating RCTs. Herein, the key finding was that: first, both early and
delayed OAC use could reduce the risk of composite and effectiveness outcomes for
each stroke severity. Second, compared with delayed use of OAC, early use, based on
the recommendations of current clinical guidelines, was not associated with an excessive
risk of composite outcomes. Third, in subjects with severe stroke, early treatment
may result in a higher bleeding risk when compared with delayed treatment, despite
presenting similar risks for the effectiveness and composite outcomes.
Previous observational studies regarding the timing of OAC initiation after AIS have
presented conflicting results. For example, Paciaroni et al have reported that the
optimal time to initiate OACs was 4 to 14 days from stroke onset.[8] Similar results have been observed in the RAF-NOAC study, with the lowest composite
rates of recurrence and major bleeding for those who initiated NOACs between 3 and
14 days.[9] The 2018 American Heart Association/American Stroke Association guidelines recommended
that secondary prevention with OACs should be appropriately instituted within the
first 2 weeks,[38] whereas United Kingdom guidelines[39] recommended that OAC administration be deferred until at least 14 days from the
onset in patients with disabling ischemic stroke.
However, more recent studies have not supported the 14-day recommendation. Yaghi et
al have conducted a registry from eight comprehensive stroke centers and found that
OACs started in the 0- to 3-day period were not associated with higher recurrent ischemic
events or ICH when compared with those initiated at 4 to 14 days.[40] Clinical Relevance of Microbleeds In Stroke-2 (CROMIS-2) also suggested that early
OAC (0–4 days) after AF-related AIS or TIA was not associated with a difference in
the composite outcome of stroke, TIA, or death at 90 days, when compared with delayed
OAC (≥5 days or never started).[41]
Given that the delayed initiation of OAC was not associated with obvious clinical
benefits, early use of OACs in mild and moderate AIS patients with AF might be a reasonable
alternative. Our finding is consistent with the previous two small randomized trials,[42]
[43] which provided reassurance regarding the safety of early initiation of administration
of rivaroxaban or dabigatran in patients with mild-to-moderate ischemic stroke (NIHSS < 9).
Previous recommendations for the delayed initiation of OAC were based on concerns
of hemorrhagic transformation after AIS. However, in our analysis, at least in subjects
with mild-to-moderate stroke severity, a delayed OAC use for secondary prevention
in patients with AF and AIS is not an evidence-based recommendation and should not
be employed as routine clinical practice; however, in severe patients with AIS, delaying
the use of OACs may reduce the risk of bleeding events. RCTs are needed to define
the appropriate timing of OACs initiation.
One of the major advantages of our study is the large study population from a nationwide
cohort, providing the opportunity to perform PS matching with sufficient event numbers
for statistical inference. Another important strength is the comprehensive analytic
framework in our study, especially the approach in dealing with immortal-time bias.
For research questions involving strategies with different timings, immortal-time
bias and confounding bias are difficult issues to resolve in observational studies.
By utilizing the day-by-day PS-matching approach, we reduced the immortal-time bias
and confounding bias when comparing different strategies. Furthermore, in the present
real-world cohorts, we employed the novel mixed treatment comparison meta-analysis
techniques for indirect comparisons to obtain relative effects of early versus delayed
OAC use in AF patients with AIS.
Several limitations of the present study need to be acknowledged. First, selection
bias is an inherent limitation of observational studies. Second, the disease status
and outcomes were identified by validated algorithms,[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[28] which might not represent patients' real conditions as the codes were designed to
claim health insurance. Third, there may be residual confounding from unmeasured or
unknown covariates as NHIRD was unable to provide laboratory data such as international
normalized ratio to evaluate the controlled efficacy of VKAs or imaging data, including
CT scan, MRI, and echocardiography, to fully evaluate the clinical status. Claims-based
databases also lack the information regarding stroke lesion volume; therefore, the
current study applied the validated tool, SSI,[25]
[26]
[27] for assessing stroke severity rather than NIHSS. The latter, however, is the most
widely accepted tool to assess the severity of stroke. Fourth, our study samples were
recruited repeatedly in different cohorts to imitate an RCT design. Our estimated
results could be confounded by unsatisfied independence. Owing to similar inclusion
criteria, methodology, and controlled variables in our study, the consistency assumption
of the indirect comparisons is less concerning.[44] Lastly, the delayed or early initiation of OACs was based on current guideline recommendations,
and future studies to determine the most appropriate timing to resume OACs are warranted.
Conclusion
In patients with AF admitted for AIS, early initiation of OACs and the routine delayed
use appeared to result in a comparable risk of composite clinical outcome across the
levels of stroke severity. The risk of bleeding events seemed to be similar for all
the OAC use groups in patients with mild-to-moderate AIS. However, such a risk was
particularly concerning for patients with severe AIS who resumed OACs early. The current
study findings support an early OAC initiation in AF patients with mild-to-moderate
AIS and a routine delayed use of OACs in those with severe AIS to avoid a serious
bleeding event. The optimal timing of OAC initiation after AIS requires further investigation.
What is known about this topic?
-
Evidence has suggested that high-risk patients with atrial fibrillation (AF) should
routinely administer lifelong oral anticoagulants (OACs) for secondary stroke prevention.
-
The 2018 European Heart Rhythm Association (EHRA) practical guide proposed a “1–3–6–12
days rule” to resume OAC after an acute ischemic stroke in patients with AF, which
is an expert consensus opinion, lacking supporting evidence from large-scale randomized
controlled trials or real-world observational studies.
What does this paper add?
-
Both early and delayed OAC uses could reduce composite and effectiveness outcomes
for each stroke severity.
-
Compared with delayed use of OAC, early use, based on the recommendations of current
clinical guidelines, was not associated with an excessive risk of composite outcomes.
-
In subjects with severe stroke, early treatment may result in a higher bleeding risk
when compared with delayed treatment, despite presenting similar risks for the effectiveness
and composite outcomes.
