Oral anticoagulants are needed in stroke patients with atrial fibrillation (AF) for the prevention of recurrent stroke. However, the risk of major events or bleeding may be greater in stroke patients than in those without, because the presence of cerebral atherosclerosis or small vessel disease may increase these risks. This study aimed to investigate the outcomes of apixaban-treated stroke patients with AF and assess whether these factors are associated with the outcome.
This was a sub-analysis of stroke patients with AF enrolled in a prospective, open-label, multicenter, post-marketing surveillance study in South Korea, who were treated with apixaban and underwent magnetic resonance imaging (MRI) (Clinical trial registration: NCT01885598).
A total of 651 patients (mean age, 72.5±8.7 years) received apixaban for a mean duration of 82.7±37.4 weeks. Fifty-three bleeding events occurred in 39 patients (6.0%), and 10 (1.5%) experienced major bleeding. Seventeen patients (2.6%) had major events (stroke, n=15, 2.3%; all ischemic), systemic embolism (n=1, 0.2%), and death (n=3, 0.5%). MRI data showed no significant association between white matter ischemic changes and microbleeds, and major events or bleeding. Patients with cerebral atherosclerotic lesions had a higher rate of major events than those without (4.6% [n=10/219] vs. 1.7% [n=7/409],
Apixaban is generally safe for patients with ischemic stroke. Increased primary outcomes in stroke patients may in part be attributed to the presence of cerebral atherosclerotic lesions, suggesting that further studies are needed to establish therapeutic strategies in this population.
Owing to their superior safety profiles, non-vitamin K antagonist oral anticoagulants (NOACs) have recently replaced warfarin for the reduction of stroke and systemic embolism risk in patients with non-valvular atrial fibrillation (AF). International guidelines now recommend NOACs as a first-line treatment option for the management of AF patients [
In 2013, apixaban received regulatory approval in South Korea for stroke and systemic embolism risk reduction in patients with AF aged ≥18 years. The current indication includes all adult patients with non-valvular AF. The approved oral dose is 5 mg twice daily (BID), while a dose reduction to 2.5 mg BID is recommended in patients with ≥2 of the following characteristics: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL. Patients with a creatinine clearance of 15 to 29 mL/min should receive a lower dose (2.5 mg BID), and apixaban is not recommended for those with creatinine clearance <15 mL/min.
Following the original marketing authorization, a key requirement of the Korean Ministry of Food and Drug Safety is that safety and effectiveness should be assessed in the setting of routine practice. Consequently, a regulatory post-marketing surveillance (PMS) study was conducted. In patients who experience a stroke associated with AF, anticoagulant therapy is recommended [
This study aimed to investigate the outcomes of patients with AF-related stroke who were treated with apixaban, and to examine whether the presence of cerebral artery atherosclerosis or SVD influences these outcomes. For this purpose, a subgroup analysis was conducted of patients with stroke who underwent brain magnetic resonance imaging (MRI) as part of the standard of care from the PMS study.
This was a sub-study of a large prospective, open-label, non-interventional, non-controlled, multicenter, observational PMS study of patients treated with apixaban as part of routine care between November 2011 and November 2017 in South Korea. Patients aged ≥18 years, diagnosed with non-valvular AF, and received apixaban therapy for the first time to reduce the risk of stroke and systemic embolism were eligible for this study. Investigators were required to use an electronic case report form to record the AF information, including the date of diagnosis, type of AF, symptoms of AF, and pulse rate, which were based on the patients’ medical records. AF duration was calculated as ‘(the informed consent date–the date of nonvalvular AF diagnosis+1)/365.25.’
Key exclusion criteria were as follows: prior treatment with apixaban; clinically significant active bleeding; coagulopathy associated with hepatic disease and clinically relevant bleeding risk; increased bleeding risk due to specific underlying diseases/conditions (recent gastrointestinal ulceration, recent intracranial hemorrhage, intraspinal or intracerebral vascular abnormalities, recent brain, spinal or ophthalmic surgery history, recent brain or spinal injury, known esophageal varices, large [>5 mm] cerebral aneurysms, malignant neoplasms with high risk of bleeding); or concomitant treatment with any other anticoagulant agent. The follow-up period was 24 months.
For this study, the principal investigators of 37 out of 56 participating sites belonging to the Department of Neurology were asked of the following: (1) to participate in this sub-study; (2) whether the patients had symptomatic ischemic stroke; and (3) whether multimodal MRI was routinely used, including diffusion-weighted imaging (DWI), fluid-attenuated inversion recovery (FLAIR), gradient echo imaging (GRE), and magnetic resonance (MR) angiography. Ultimately, 21 sites agreed to participate (
Prior to patient enrollment, the writing committee members established an additional three-page data sheet that included the location of the relevant ischemic lesion detected by DWI at the time of enrollment, presence and degree of WMH on FLAIR (Fazekas scale) [
Most patients were treated based on the approved doses of apixaban at 2.5 or 5 mg orally BID. However, off-label dosing was allowed based on clinical judgment. Treatment could be discontinued at any time at the discretion of the investigator. The study was conducted in accordance with the Declaration of Helsinki, the International Society for Pharmacoepidemiology Guidelines for Good Pharmacoepidemiology Practices, and other regulatory requirements. Approval was granted at individual sites by local ethics committees, independent review committees, regulatory authorities, and/or other government bodies. All subjects provided written consent prior to enrollment. The trial was registered at clinicaltrials.gov (Clinical trial registration:
Follow-up visits were scheduled at 3, 6, 12, and 24 months after enrollment. Patient medical records were the data sources for the study variables. Baseline assessments included sex, age, body weight, blood pressure, serum creatinine, creatinine clearance, smoking history, and AF type and duration. MRI data were obtained as described above. During the study period, the apixaban dose and treatment duration were recorded. All instances of major bleeding, defined as any bleeding event that necessitated temporary or permanent apixaban discontinuation or dose reduction, were documented. Major events, defined as stroke of any type, systemic embolism, or death, were also recorded. Detailed information on recurrent stroke was captured on an additional three-page data sheet by the investigators (
Statistical analyses were performed using SAS, release 9.3 or higher (SAS Institute Inc., Cary, NC, USA). Descriptive statistics were provided, including mean±standard deviation and range for continuous variables, and frequency and percentage for categorical variables. Associations between apixaban dosing regimen and rates of major events or major bleeding were assessed using Fisher’s exact test. Those between baseline characteristics or imaging findings and rates of major events or major bleeding were assessed using either Fisher’s exact test or the chi-square test. Statistical significance was set at
Case report forms were collected from apixaban-treated subjects enrolled in the study. The present analysis included data from 651 patients with AF and ischemic stroke assessed using brain MRI. Baseline characteristics are shown in
MRI findings showed that 64.3% of the patients had WMH changes (Fazekas grade 1, 42.2%; grade 2, 14.7%; grade 3, 7.4%). A total of 82 patients (13.3%) had microbleeds. Nineteen (3.1%) and 63 (10.2%) patients had ≥5 and <5 microbleeds, respectively. Nineteen patients (3.0%) had aneurysms (≤5 mm). Two hundred nineteen patients (34.9%) had cerebral atherosclerotic lesions, with 151 having intracranial atherosclerosis, 41 having extracranial atherosclerosis, and 58 having both (
The apixaban dose was recorded in 649 patients (
Fifty-three adverse events of bleeding were recorded in 39 patients (6.0%). Ten patients (1.5%) experienced major bleeding (without intracerebral hemorrhage), leading to complete or temporary discontinuation of apixaban in two and three patients, respectively, and a dose reduction in six cases. In total, 17 patients (2.6%) experienced major events during the follow-up period. Fifteen (2.3%) developed a stroke (all were ischemic), one (0.2%) had a systemic embolism, and three (0.5%) expired (
Although MRI was performed in all 15 patients who developed recurrent stroke, the status was evaluable in 13 individuals (
An analysis of MRI data demonstrated no significant association between WMH, microbleeds, or aneurysm and rates of major events (stroke, systemic embolism, or death) or major bleeding (
There were no significant associations between overall rates of major events (stroke, systemic embolism, or death assessed separately), rates of major bleeding, and patients’ left ventricular ejection fraction (≤30% vs. >30%) or valvular abnormalities (present vs. absent) on echocardiography (data not shown).
Major bleeding rates were significantly higher in individuals receiving off-label reduced-dose apixaban (n=7/59, 11.9%) than in those receiving on-label standard dose (n=1/488, 0.2%), on-label reduced dose (n=2/95, 2.1%), or off-label increased dose (n=0/7, 0%) (
Of the 16 patients who experienced a major event and for whom there was information regarding the prescribed dose, nine received on-label apixaban standard dose (5 mg BID), five were given on-label reduced dose (2.5 mg BID), and two received an off-label reduced dose. None of the 16 patients received an off-label increased dose. Hence, the rates of major events were 1.8% (n=9/488) in the on-label standard-dose group, 5.3% (n=5/95) in the on-label reduced dose group, 3.4% (n=2/59) in the off-label reduced dose group, and 0% (n=0/7) in the off-label increased dose group (
Exploratory analyses were performed to compare the rates of major bleeding and major events in the present subgroup of patients (with a symptomatic ischemic stroke) versus another subgroup of patients enrolled in the same study who had no symptomatic ischemic stroke (n=1,711). Patients with stroke were significantly older and showed higher rates of dyslipidemia and cigarette smoking than those without. The rate of major events was also higher in patients with stroke than in those without (2.6% [n=17/651] vs. 0.7% [n=12/1711], respectively;
This study was a sub-analysis of data from 651 patients with AF-associated symptomatic stroke, who were treated with apixaban in the context of routine clinical practice, and additional MRI records. The 1.5% overall rate of major bleeding was broadly in line with previously reported clinical trial data in AF [
An exploratory analysis of the present patient population showed that rates of major events, but not major bleeding, were higher in patients with symptomatic ischemic stroke than in those without. This result is similar with a sub-analysis of the Japanese PMS study, in which apixaban-treated AF patients with ischemic stroke or transient ischemic attack experienced significantly higher rates of thromboembolic and hemorrhagic events than those without [
In the current study, patients with stroke were older and more often had vascular risk factors such as hyperlipidemia or smoking than in those without, which may have contributed to the higher incidence of major events (
A previous study showed that the presence of intracranial atherosclerosis is independently associated with the risk of subsequent vascular events in patients with ischemic stroke [
Three of four patients (75.0%) whose recurrent stroke was potentially related to large artery disease had cerebral artery atherosclerosis on initial imaging, while 55.6% of patients with recurrent stroke, probably due to cardiac embolism, had cerebral artery atherosclerosis. Due to the small number of patients who developed a recurrent stroke, it could not be clearly explored whether the recurrent strokes in these patients were primarily atherosclerotic in nature. Nevertheless, our results suggest that patients with atherosclerotic cerebral arteries are at an increased risk of recurrent stroke, and therefore, require more careful follow-up. Whether additional use of antiplatelet agents is needed in AF patients with concurrent cerebral atherosclerosis remains to be investigated.
WMH and microbleeds have been previously linked with an elevated risk of ischemic stroke or hemorrhage [
An evaluation based on apixaban dosing found that the major bleeding rate was significantly higher in patients treated with an off-label reduced apixaban dose (11.9%,
There are some limitations to this study. First, this was a single-arm observational study without a control group, performed in the context of routine practice. This inevitably limits the value of the safety and effectiveness data in this study. Second, this sub-analysis was based on patients with additional MRI records, and thus reducing the population size and the number of patients who experienced major events. Therefore, the results obtained here should be interpreted with caution. Finally, in this multicenter, practical study, MRI technologies were not homogeneous, and imaging findings were interpreted by local investigators.
Our results showed that the effectiveness and safety of apixaban for reducing the risk of stroke and systemic embolism in Korean patients with AF in routine clinical practice was consistent with the results of the ARISTOTLE trial. MRI data from this population showed that the rate of stroke was significantly increased in patients with cerebral artery atherosclerosis, suggesting that special care is required in these individuals. Off-label reduced dosing may be associated with worse outcomes, and thus compelling the use of on-label recommended dosing in real-life practice.
Supplementary materials related to this article can be found online at
This study was funded by Pfizer Inc. and Bristol Myers Squibb and conducted by Bristol Myers Squibb Korea.
Jong S. Kim reports receiving grants from Dong-A, Pfizer, Servier, Daiichi-Sankyo, and Shin-Poong outside of the submitted work. Keun-Sik Hong reports receiving grants from Bristol Myers Squibb (BMS) Korea Ltd. during the conduct of the study, grants from BMS Korea, Boryung Pharmaceutical, and Hanmi Pharm outside of the submitted work, and lecture honoraria from BMS Korea and Daiichi Sankyo Korea outside of the submitted work. Hyeju Yi is an employee of Bristol Myers Squibb, Korea. The authors have no conflicts of interest to declare.
We thank all 23 institutions and co-investigators who actively participated in this study. Medical writing and editorial support were provided by Soyoung Park of PPC Korea and Cathy Chow, PhD, of Weber Shandwick Hong Kong.
Patient flowchart. AF, atrial fibrillation; PMS, post-marketing surveillance.
Baseline characteristics
Characteristic | Patients (n=651) |
---|---|
Female ex | 270 (41.5) |
Age (yr) | 72.5±8.7 (40–94) |
Body weight (kg) (n=571) | 62.9±11.4 (34–98) |
Creatinine clearance (mL/min) (n=568) | 64.2±23.0 (14.2–151.5) |
Hypertension | 444 (68.2) |
Diabetes | 146 (22.4) |
Dyslipidemia | 230 (35.3) |
Current smoker | 118 (18.1) |
Statin co-administered | 455 (69.9) |
Duration of AF (yr) (n=475) | 2.8±3.8 (0–23.0) |
Left ventricular ejection fraction (%) (n=461) | 59.8±10.4 (16.0–86.0) |
Valvular abnormality |
216 (46.7) |
Apixaban dose (n=649) | |
On-label standard dose (5 mg BID) | 488 (75.2) |
On-label reduced dose (2.5 mg BID) | 95 (14.6) |
Off-label reduced dose | 59 (9.1) |
Off-label increased dose | 7 (1.1) |
Duration of apixaban treatment (wk) (n=578) | 82.7±37.4 (0.1–126.0) |
Values are presented as number (%) or mean±standard deviation (range).
AF, atrial fibrillation; BID, twice daily.
Mitral or aortic valve regurgitation/stenosis.
MRI findings and major events or major bleeding
MRI finding | Total patients | Major events |
Stroke | Systemic embolism | Death | Major bleeding | ||
---|---|---|---|---|---|---|---|---|
White matter ischemic change, Fazekas scale (n=580) | ||||||||
0 | 207 | 6 (2.9) | 6 (2.9) | 0 (0) | 2 (1.0) | 3 (1.4) | ||
1 | 245 | 7 (2.9) | 6 (2.4) | 1 (0.4) | 0 (0) | 6 (2.4) | ||
2 | 85 | 1 (1.2) | 1 (1.2) | 0 (0) | 0 (0) | 1 (1.2) | ||
3 | 43 | 2 (4.7) | 2 (4.7) | 0 (0) | 0 (0) | 0 (0) | ||
- | 0.6577 | 0.6422 | 1.0000 | 0.5200 | 0.7859 | |||
Microbleeds (n=615) | ||||||||
Yes (≥5) | 19 | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | ||
Yes (<5) | 63 | 3 (4.8) | 2 (3.2) | 1 (1.6) | 0 (0) | 1 (1.6) | ||
No | 533 | 13 (2.4) | 13 (2.4) | 0 (0) | 2 (0.4) | 7 (1.3) | ||
- | 0.4342 | 0.7928 | 0.1333 | 1.0000 | 0.6840 | |||
Aneurysm (n=629) | ||||||||
Yes | 19 | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | ||
No | 610 | 17 (2.8) | 15 (2.5) | 1 (0.2) | 3 (0.5) | 10 (1.6) | ||
- | 1.0000 | 1.0000 | 1.0000 | 1.0000 | 1.0000 | |||
Atherosclerotic arterial lesion (n=628) | ||||||||
Yes | 219 | 10 (4.6) | 9 (4.1) | 0 (0) | 1 (0.5) | 4 (1.8) | ||
Intracranial | 120 | 4 (3.3) | 4 (3.3) | 0 (0) | 0 (0) | 1 (0.8) | ||
Extracranial | 41 | 3 (7.3) | 2 (4.9) | 0 (0) | 1 (2.4) | 1 (2.4) | ||
Both | 58 | 3 (5.2) | 3 (5.2) | 0 (0) | 0 (0) | 2 (3.5) | ||
No | 409 | 7 (1.7) | 6 (1.5) | 1 (0.2) | 2 (0.5) | 6 (1.5) | ||
- | 0.0357 |
0.0387 |
1.0000 |
1.0000 |
0.7454 |
Values are presented as number (%).
MRI, magnetic resonance imaging.
Stroke, systemic embolism, or death;
Fisher’s exact test;
Chi-square test.
Bleeding and major events (total events=53)
Variable | No. of patients (%) |
---|---|
Bleeding (adverse event) | 39 (6.0) |
Major bleeding | 10 (1.5) |
Major events | |
All | 17 (2.6) |
Stroke | 15 (2.3) |
Systemic embolism | 1 (0.2) |
Death | 3 (0.5) |
MRI results and possible stroke pathogenesis in evaluable patients who developed recurrent stroke
MRI results | Patients (n=13) |
---|---|
DWI | |
Single lesion (corticosubcortical) | 1 |
Single lesion (cortical) | 3 |
Single lesion (subcortical or brainstem [≤15 mm]) | 1 |
Single lesion (subcortical or brainstem [>15 mm]) | 0 |
Multiple scattered (1 vessel territory) | 3 |
Multiple scattered (>1 vessel territory) | 2 |
Missing data | 3 |
GRE |
|
Have ‘microbleeds’ increased from previous image? | |
Yes | 1 |
No | 11 |
Missing data | 1 |
Stroke pathogenesis | |
Is it possible that the stroke event was caused by large-artery disease? | |
Yes | 4 |
No | 9 |
Is it possible that the stroke event was caused by small-vessel disease? | |
Yes | 1 |
No | 12 |
Cerebral artery atherosclerosis at baseline MRI | |
Yes | 8 |
Intracranial | 4 |
Extracranial | 1 |
Both | 3 |
No | 5 |
MRI, magnetic resonance imaging; DWI, diffusion-weighted imaging; GRE, gradient-recalled echo.
GRE identified two cases of hemorrhagic transformation.
Comparison of major events and major bleeding between patients with symptomatic ischemic stroke and those without
Characteristic | Patients with symptomatic ischemic stroke (Department of Neurology, n=651) | Patients without symptomatic ischemic stroke (Department of Cardiology, n=1,711) | ||
---|---|---|---|---|
Age (yr) | 72.5±8.7 | 70.0±10.4 | <0.0001 |
|
Male sex | 381 (58.5) | 965 (56.4) | 0.3587 |
|
Current smoking, yes | 118 (18.1) | 248 (14.5) | 0.0306 |
|
Diabetes, yes | 146 (22.4) | 444 (26.0) | 0.0772 |
|
Dyslipidemia, yes | 230 (35.3) | 433 (25.3) | <0.0001 |
|
Hypertension, yes | 444 (68.2) | 1,168 (68.3) | 0.9771 |
|
Major events | ||||
All | ||||
Yes | 17 (2.6) | 12 (0.7) | 0.0002 |
|
No | 634 (97.4) | 1,699 (99.3) | ||
Stroke | ||||
Yes | 15 (2.3) | 9 (0.5) | 0.0001 |
|
No | 636 (97.7) | 1,702 (99.5) | ||
Systemic embolism | ||||
Yes | 1 (0.2) | 1 (0.1) | 0.4753 |
|
No | 650 (99.8) | 1,710 (99.9) | ||
Death | ||||
Yes | 3 (0.5) | 2 (0.1) | 0.1321 |
|
No | 648 (99.5) | 1,709 (99.9) | ||
Major bleeding | ||||
Yes | 10 (1.5) | 24 (1.4) | 0.8078 |
|
No | 641 (98.5) | 1,687 (98.6) |
Values are presented as mean±standard deviation or number (%).
Wilcoxon’s rank sum test;
Chi-square test;
Fisher’s exact test.
Comparison between patients with symptomatic ischemic stroke without cerebral atherosclerosis and patients without ischemic stroke
Characteristic | Patients with symptomatic ischemic stroke without the presence of cerebral atherosclerosis (Department of Neurology) (n=432) | Patients without symptomatic ischemic stroke (Department of Cardiology) (n=1,711) | ||
---|---|---|---|---|
Age (yr) | 71.6±8.7 | 70.0±10.4 | 0.0137 |
|
Male sex | 251 (58.1) | 965 (56.4) | 0.5315 |
|
Smoking history, yes | 70 (16.2) | 248 (14.5) | 0.3794 |
|
Diabetes, yes | 88 (20.4) | 444 (26.0) | 0.0165 |
|
Dyslipidemia, yes | 151 (35.0) | 433 (25.3) | <0.0001 |
|
Hypertension, yes | 280 (64.8) | 1,168 (68.3) | 0.1712 |
|
Major events | ||||
All | ||||
Yes | 7 (1.6) | 12 (0.7) | 0.0828 |
|
No | 425 (98.4) | 1,699 (99.3) | ||
Stroke | ||||
Yes | 6 (1.4) | 9 (0.5) | 0.0962 |
|
No | 426 (98.6) | 1,702 (99.5) | ||
Systemic embolism | ||||
Yes | 1 (0.2) | 1 (0.1) | 0.3626 |
|
No | 431 (99.8) | 1,710 (99.9) | ||
Death | ||||
Yes | 2 (0.5) | 2 (0.1) | 0.1831 |
|
No | 430 (99.5) | 1,709 (99.9) | ||
Major bleeding | ||||
Yes | 6 (1.4) | 24 (1.4) | 0.9826 |
|
No | 426 (98.6) | 1,687 (98.6) |
Values are presented as number (%).
Wilcoxon’s rank sum test;
Chi-square test;
Fisher’s exact test.
10. Initial stroke admission note | |||||||
1. Did your patient have symptomatic ischemic stroke? | |||||||
□ Yes (□ Single event / □ Multiple) □ No | |||||||
Mechanism (by TOAST criteria, multiple choice): | |||||||
□ LAD □ CE □ SVD □ Undetermined □ Other determined □ Unknown | |||||||
2. MRI | DWI | Single lesion: | □ Cortico-subcortical □ Cortical | ||||
□ Subcortical or brainstem (□ ≤15 mm / □ >15 mm) | |||||||
Multiple scattered: | □ 1 vessel territory □ More than 1 vessel territory | ||||||
GRE, FLAIR | Microbleeds: | □ Yes (□≥ 5 □< 5) □ No | |||||
Hemorrhagic transformation: | □ Yes (□HI1 □HI2 □PH1 □PH2) (Fiorelli 1999) □ No | ||||||
White mater ischemic change: | Fazeka’s scale (□ 0 □ 1 □ 2 □ 3) | ||||||
Angiography (CTA, MRA, TFCA) | Is there an aneurysm? □ Yes □ No | ||||||
Can you observe atherosclerotic steno-occlusion? □ Yes ↓ (Please check below.) □ No | |||||||
→ Atherosclerosis related to the infarct: □ Intracranial □ Extracranial □ Both | |||||||
→ Atherosclerosis unrelated to the infarct: □ Intracranial □ Extracranial □ Both | |||||||
→ Do both atherosclerosis (related/not related to the infarct) exist? □ Yes □ No | |||||||
3. Is there a possibility that this stroke event is small vessel disease? | |||||||
□ Yes □ No | |||||||
4. Laboratory test data at the time of stroke event. | |||||||
Test Item | Test Date | Test Result | Normal range | Test Item | Test Date | Test Result | Normal range |
WBC | 103/uL | Hb | g/dL | ||||
Platelet | 103/uL | PT | |||||
CRP | mg/dL | INR | |||||
d-dimer | ug/mL | ||||||
5. Echocardiography result | |||||||
(If test result 3 months before/after hospitalization exists, answer to the questions below. If there are several test results, please choose the result closest to the stroke event.) | |||||||
Was Echocardiography conducted? □ Yes ↓ (Please check below.) □ No | |||||||
→ LV Ejection Fraction: ( ) % | |||||||
→ Valvular abnormalities (in case of trace, please check “No”.) | |||||||
Mitral valve regurgitation □ Yes, Gr(□ 1 □ 2 □ 3 □ 4 or □ mild □ moderate □ severe) □ No | |||||||
Mitral valve stenosis □ Yes, MVA (2D/PHT): ( / ) cm2 □ No | |||||||
Aortic valve regurgitation □ Yes, Gr(□ 1 □ 2 □ 3 □ 4 or □ mild □ moderate □ severe) □ No | |||||||
Aortic valve stenosis □ Yes, AVA (2D/Doppler): ( / ) cm2 □ No | |||||||
→ LA diameter ( ) mm | |||||||
□ Death ↓ (Please fill in the `death’ item below) | |||||||
□ Stroke → (□ Ischemic stroke ↓ □ Hemorrhagic stroke □ Uncertain) | |||||||
□ Systemic embolism | |||||||
□ Bleeding ↓ (Please fill in the bleeding items below) | |||||||
□ Other events ↓ (Please fill in the other events item below) | |||||||
Bleeding Site | □ Intracranial → (□ Intracerebral hemorrhage, □ Subarachnoid hemorrhage, □ Subdural Hemorrhage, □ Others) | ||||||
□ Intramedullary □ Intraocular □ Intrapericardial □ Intra-articular □ Intramuscular □ Retroperitoneal | |||||||
□ Digestive tract □ Others (______________________________________) | |||||||
Time of Bleeding | □ When switching from another anticoagulant to Eliquis® | ||||||
□ When switching from Eliquis® to another anticoagulant | |||||||
□ During medical intervention □ During thrombolytic therapy | |||||||
□ When continuously using Eliquis® | |||||||
□ Others (______________________________________) | |||||||
Is there a decrease in hemoglobin ≥2g/dL ? | □ Yes | Was transfusion of whole blood and/or packed RBC done ? | □ Yes →_____Unit | ||||
□ No | □ No | ||||||
What are the factors other than Eliquis® considered to affect stroke, systemic embolism or bleeding? | □ Yes ↓ | ||||||
(□ Atrial fibrillation □ Complication _______ □ Concomitant drug ______ □ Others ______) | |||||||
□ No | |||||||
Ischemic stroke | 1. Can you assess patient’s status? | ||||||
□ Yes ↓ (Please fill in the below.) □ No (assessment is not feasible due to transfer to another hospital, etc.) | |||||||
2. Neurologic status | |||||||
□ Admission NIHSS □ Admission mRS □ Discharge NIHSS □ Discharge mRS | |||||||
3. MRI | 3-1. DWI | Single lesion: | □ Cortico-subcortical □ Cortical | ||||
□ Subcortical or brainstem (□ ≤15 mm / □ >15 mm) | |||||||
Multiple scattered: | □ 1 vessel territory □ More than 1 vessel territory | ||||||
3-2. GRE, FLAIR | Compared to previous image, were microbleeds increased? □ Yes □ No | ||||||
Hemorrhagic transformation: □ Yes (□ HI1 □ HI2 □ PH1 □ PH2) □ No | |||||||
4. Is there a possibility that this stroke event is due to large artery disease? | |||||||
□ Yes □ No | |||||||
5. Is there a possibility that this stroke event is due to small vessel disease? | |||||||
□ Yes □ No | |||||||
6. Laboratory Test Data at the time of stroke event. | |||||||
Test item | Test date | Test result | Test item | Test date | Test result | ||
WBC | 103/uL | Hb | g/dL | ||||
Platelet | 103/uL | PT | |||||
CRP | mg/dL | INR | |||||
d-dimer | ug/mL | ||||||
Death | □ VTE-related death | ||||||
□ Non VTE-related cardiovascular death | |||||||
□ Death related to myocardial infarction | |||||||
□ Death related to stroke | |||||||
□ Death related to cardiovascular disease | |||||||
□ Death related to major bleeding | |||||||
Other events | □ Myocardial infarction | ||||||
□ Other cardiovascular disease ; ________________________________ (diagnosis) | |||||||
Was intervention or medication given for the major event? | □ Yes → Please describe the detail in the “Medical Intervention, Medication of Anticoagulant other than Eliquis®, Concomitant Medication Status” section. | ||||||
□ No |
[Major Event Occurrence Status]
Please fill in the below events until the end of study.