Abstract
Background:
The international Randomized, Double-Blind, Evaluation in Secondary Stroke Prevention Comparing the EfficaCy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate versus Acetylsalicylic Acid in Patients with Embolic Stroke of Undetermined Source (RE-SPECT ESUS) trial did not demonstrate superiority of dabigatran over aspirin for reduction of recurrent strokes in patients with embolic strokes of undetermined source (ESUS). Based on pre-defined subanalyses, the safety and efficacy of dabigatran vs. aspirin in Japanese patients was assessed.
Methods and Results:
ESUS patients were randomized to receive either dabigatran (150 or 110 mg twice daily) or aspirin (100 mg once daily). Of 5,390 patients randomized, 594 were Japanese. Most Japanese patients (99.8%) underwent brain magnetic resonance imaging for trial screening, compared to 76.8% of non-Japanese (P<0.0001). In the Japanese cohort, over a 19.4-month median follow-up period, recurrent stroke as the primary outcome occurred in 20/294 patients (4.3%/year) in the dabigatran group and 38/300 (8.3%/year) in the aspirin group (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.32–0.94). Major bleeding occurred in 12 patients (2.5%/year) and 17 patients (3.5%/year), respectively (HR, 0.72; 95% CI, 0.34–1.52). In contrast, in the non-Japanese cohort, recurrent stroke occurred in 4.1%/year and 4.3%/year, respectively, showing no apparent difference in recurrent stroke for dabigatran vs. aspirin (HR, 0.91; 95% CI, 0.74–1.14). The P-interaction for treatment and region did not reach statistical significance (P=0.09).
Conclusions:
Dabigatran was putatively associated with a lower relative risk of recurrent stroke compared with aspirin in Japanese ESUS patients.
Ischemic stroke is the most common type of stroke in Japan, accounting for 66–75% of strokes in a recent analysis of a large population-based registry.1
Approximately 25% of ischemic strokes have been categorized as cryptogenic.2
Embolic stroke of undetermined source (ESUS) is a subset of cryptogenic strokes defined based on brain imaging that suggests an embolic etiology, without relevant arterial stenoses or other cardiac sources, and with no other specific known cause identified after a specified series of tests.3
Antiplatelet agents, such as aspirin, are recommended in guidelines for secondary stroke prevention in patients with cryptogenic stroke.4,5
Oral anticoagulants, including dabigatran etexilate, have an established role in preventing strokes among patients with non-valvular atrial fibrillation (AF), which represents a high-risk cardiac source of embolism.6
In the international RE-SPECT ESUS trial, over a median of 19 months’ follow up, dabigatran was not superior to aspirin in reducing recurrent strokes (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.69–1.03; P=0.10), and the incidence of major bleeding was similar between treatments (HR, 1.19; 95% CI, 0.85–1.66).7
Rivaroxaban was also not superior to aspirin in the treatment of ESUS patients in another randomized trial.8
Thus, direct oral anticoagulants have not been recommended for secondary prevention of stroke in ESUS patients.
In global clinical trials, differences in intrinsic and extrinsic ethnic factors, such as patient demographics and the diagnostic process of ESUS between regions, may affect the safety and efficacy of medications. Therefore, region-specific assessments are important; although they are usually underpowered, they are hypothesis-generating. In particular, the routine use of magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) in the acute setting of stroke care in Japan seems to improve the accurate diagnosis of stroke subtypes, including ESUS. The objective of the current, pre-specified analysis was to assess the safety and efficacy outcomes from the RE-SPECT ESUS study involving Japanese patients randomized to receive either dabigatran or aspirin treatment.
Methods
Study Design and Participants
Randomized, Double-Blind, Evaluation in Secondary Stroke Prevention Comparing the EfficaCy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate versus Acetylsalicylic Acid in Patients with Embolic Stroke of Undetermined Source (RE-SPECT ESUS) was an international, double-blind, parallel-group, randomized trial. Patients were enrolled from December 2014 to January 2018 in 42 countries. The trial was approved by the ethics committees at all sites, and patients provided written informed consent to participate. An independent adjudication committee, unaware of treatment assignments, reviewed and classified primary and secondary efficacy outcomes and major bleeding events. The study design and methods have been published elsewhere.9
Patients were eligible if they were aged ≥60 years and had experienced an ESUS within the prior 3 months, or within the prior 6 months if they had at least one additional vascular risk factor; or if they were aged 18–59 years (20–59 years in Japan according to a local protocol amendment) and had at least one additional vascular risk factor and experienced a qualifying stroke within the prior 3 months.
ESUS was defined as:3
non-lacunar ischemic stroke detected by computed tomography (CT) or MRI; absence of extracranial or intracranial atherosclerosis causing ≥50% stenosis in arteries supplying the area of the stroke, as detected by arterial imaging or cervical and transcranial Doppler ultrasonography; absence of AF of >6 min in duration10
evaluated by cardiac monitoring for ≥20 h; absence of intracardiac thrombus by transthoracic or transesophageal echocardiography; and no other specific cause of stroke identified.
Treatment
Patients were assigned 1 : 1 to dabigatran or to aspirin 100 mg once daily (non-enteric-coated form) (Supplementary Figure). Dabigatran doses were 150 mg twice daily, or 110 mg twice daily in patients aged ≥75 years or with an estimated creatinine clearance of ≥30 to ≤50 mL/min; this differs from the labelled dose recommendations for patients with non-valvular AF in Japan, where ≥70 years is a criterion for the lower dose. Patients with coronary artery disease could receive aspirin if they were assigned to the dabigatran group, or placebo if assigned to the aspirin group. Treatment was planned for at least 6 months and up to 3.5 years.
Outcomes
The primary efficacy outcome was time to first recurrent stroke of any type (ischemic, hemorrhagic, or unspecified). The main safety outcome was time to first major bleeding according to International Society on Thrombosis and Haemostasis (ISTH) criteria.11
Secondary efficacy outcomes and other safety outcomes are reported in the
Results.
Statistical Analysis
Baseline characteristics, efficacy, and safety outcomes were analyzed for the intention-to-treat population (randomized set), and adverse events (AEs) were analyzed for the treated set, with censoring of patients lost to follow up on the last day their status was known. A Cox proportional hazards regression model was used for the analysis of outcomes, adjusting for age, renal impairment, and transient ischemic attack or stroke prior to the index stroke (SAS version 9.4; SAS Institute, Cary, NC, USA). Results were analyzed separately for the cohort of Japanese patients registered in Japan (“Japanese patients”) and for the remainder of the registered patients (“non-Japanese patients”). In this subanalysis, Japanese patients were analyzed using treatment-by-subgroup tests for interaction to evaluate consistency of results for the primary efficacy outcome.
Results
Participants and Follow up
A total of 5,390 patients were randomized to receive either dabigatran or aspirin treatment. From 63 hospital sites in Japan (Supplementary Table 1), 594 Japanese patients were randomized to receive either dabigatran or aspirin treatment. One patient in the dabigatran group did not receive treatment (Figure 1). No Japanese patients were screened from outside Japan.
Comparing the Japanese with the non-Japanese cohort (n=4,796), patients from Japan were older (P<0.0001) and had a lower body mass index (P<0.0001) (Table 1). Patients from Japan were also more likely to drink alcohol (P<0.0001), have renal insufficiency (creatinine clearance <50 mL/min, P<0.0001), have a mild index stroke according to the National Institutes of Health Stroke Scale score (ranging from 0 to 42, with higher scores indicating worse neurologic deficits) of 0–4 (P<0.0001), and have less pre-stroke disability (modified Rankin Scale score [ranging from 0 to 6, with higher scores indicating worse functional deficits] of 0–1, P<0.0001]. Prior myocardial infarction (P<0.0001) and coronary artery disease (P<0.0001) were less common, and prior stroke was more common (P<0.0001) in the Japanese than the non-Japanese cohort. For trial screening, all but 1 Japanese patient (99.8%) had a brain MRI, with brain CT used for the remaining patient; brain MRI was used in 3,681 (76.8%) non-Japanese patients (P<0.0001).
Table 1.
Patient Baseline Characteristics in the Japanese and Non-Japanese Cohorts
| Characteristic |
Japanese
(n=594) |
Non-Japanese
(n=4,796) |
P valuea |
| Age, years |
67.4±10.3 |
63.8±11.5 |
<0.0001 |
| Female |
196 (33.0) |
1,791 (37.3) |
0.0427 |
| Body mass index, kg/m2 b |
23.8±3.5 |
27.7±5.0 |
<0.0001 |
| Systolic blood pressure, mmHg |
133.9±16.7 |
132.0±15.7 |
0.0095 |
| Diastolic blood pressure, mmHg |
78.5±11.0 |
78.5±9.9 |
0.9727 |
| Current smokerc |
82 (13.8) |
809 (16.9) |
0.0643 |
| Current drinkerc |
367 (61.8) |
2,498 (52.1) |
<0.0001 |
| Creatinine clearance <50 mL/mind |
111 (18.7) |
319 (6.7) |
<0.0001 |
| Time from index stroke to randomization, daysc |
43 [25–73] |
44 [20–81] |
0.5084 |
| CHA2DS2-VASc score ≥5 |
251 (42.3) |
1,941 (40.5) |
0.4289 |
| Modified Rankin scale score 0–1 |
500 (84.2) |
3,186 (66.4) |
<0.0001 |
| National Institutes of Health Stroke Scale score 0–4e |
584 (98.3) |
4,398 (91.7) |
<0.0001 |
| Medical history |
| Previous transient ischemic attack |
33 (5.6) |
262 (5.5) |
1.0000 |
| Previous stroke |
145 (24.4) |
587 (12.2) |
<0.0001 |
| Previous myocardial infarction |
10 (1.7) |
330 (6.9) |
<0.0001 |
| Coronary artery disease |
19 (3.2) |
558 (11.6) |
<0.0001 |
| Previous atrial fibrillation |
2 (0.3) |
5 (0.1) |
0.3789 |
| Hypertension |
424 (71.4) |
3,557 (74.2) |
0.1592 |
| Diabetes mellitus |
117 (19.7) |
1,107 (23.1) |
0.0710 |
| Hyperlipidemia |
304 (51.2) |
2,739 (57.1) |
0.0068 |
| Patent foramen ovalec |
66 (11.1) |
614 (12.8) |
0.2689 |
| Left ventricular dysfunction or ejection fraction ≤40%c |
6 (1.0) |
65 (1.4) |
0.6133 |
| Use of imaging tools for trial screening |
| Brain magnetic resonance imaging |
593 (99.8) |
3,681 (76.8) |
0.0001 |
| Brain magnetic resonance angiography |
551 (92.8) |
2,004 (41.8) |
<0.0001 |
| Transesophageal echocardiography |
187 (31.5) |
1,459 (30.4) |
0.6550 |
Values are presented as n (%), mean±standard deviation, or median [interquartile range]. aP values are from: t-test for age, weight, and body mass index; Wilcoxon rank-sum test for time from index stroke to randomization; and chi-squared test for others. bData missing for 1 patient in the Japanese group and 40 in the non-Japanese group. cData missing for 1 patient each in the Japanese group and the non-Japanese group. dData missing for 5 patients in the non-Japanese group. eData missing for 11 patients in the non-Japanese group.
Baseline clinical and demographic characteristics appeared to be mostly similar between the 2 treatment groups in the Japanese cohort (Table 2). In addition to the minimum required 20 h of electrocardiogram (ECG) monitoring, extended ECG monitoring was performed in 22 patients (7.5%) in the dabigatran group and in 54 (18.0%) in the aspirin group. AF with a cumulative duration over the monitoring period of >6 min was diagnosed after randomization in 2 (0.7%) and 3 (1.0%) patients, respectively.
Table 2.
Baseline Characteristics of the Japanese Patients by Two Treatment Groups
| Characteristic |
Dabigatran
(n=294) |
Aspirin
(n=300) |
| Age, years |
67.1±10.7 |
67.7±9.9 |
| Female |
100 (34.0) |
96 (32.0) |
| Body mass index, kg/m2 a |
23.7±3.4 |
23.8±3.6 |
| Systolic blood pressure, mmHg |
133.5±16.3 |
134.3±17.1 |
| Diastolic blood pressure, mmHg |
78.5±10.9 |
78.4±11.1 |
| Current smoker |
46 (15.6) |
36 (12.0) |
| Current drinker |
181 (61.6) |
186 (62.0) |
| Creatinine clearance <50 mL/min |
51 (17.3) |
60 (20.0) |
| Time from index stroke to randomization, days |
43 [23–73] |
43 [26–73.5] |
| CHA2DS2-VASc score ≥5 |
121 (41.2) |
130 (43.3) |
| Modified Rankin scale score 0–1 |
244 (83.0) |
256 (85.3) |
| National Institutes of Health Stroke Scale score 0–4 |
288 (98.0) |
296 (98.7) |
| Medical history |
| Previous transient ischemic attack |
15 (5.1) |
18 (6.0) |
| Previous stroke |
70 (23.8) |
75 (25.0) |
| Previous myocardial infarction |
4 (1.4) |
6 (2.0) |
| Coronary artery disease |
8 (2.7) |
11 (3.7) |
| Previous atrial fibrillation |
1 (0.3) |
1 (0.3) |
| Hypertension |
205 (69.7) |
219 (73.0) |
| Diabetes mellitus |
56 (19.0) |
61 (20.3) |
| Hyperlipidemia |
143 (48.6) |
161 (53.7) |
| Patent foramen ovaleb |
30 (10.2) |
36 (12.0) |
| Left ventricular dysfunction or ejection fraction ≤40% |
2 (0.7) |
4 (1.3) |
| Use of brain magnetic resonance imaging for trial screening |
294 (100.0) |
299 (99.7) |
Values are presented as n (%), mean±standard deviation, or median [interquartile range]. aData missing for 1 patient in the dabigatran group. bData missing for 1 patient in the aspirin group.
Patients assigned to receive dabigatran were followed for a median of 19.1 (range: 0–37) months, and aspirin patients for a median of 20.5 (range: 5–37) months. Trial medication was discontinued prematurely by 77 (26.2%) and 72 (24.0%) patients in the dabigatran and aspirin groups (P=0.5381), respectively, mostly due to adverse events (56 and 58 patients, respectively). The vital status of three patients was not available (Figure 1).
Efficacy Outcomes
In the Japanese cohort, first recurrent stroke occurred in fewer patients in the dabigatran group (20 [6.8%; 4.3%/year]) than in the aspirin group (38 [12.7%; 8.3%/year]) (HR, 0.55; 95% CI, 0.32–0.94) (Table 3, Figure 2). First recurrent strokes were ischemic, except for 2 patients in the aspirin group who had hemorrhagic stroke (one each of intracerebral and subarachnoid).
Table 3.
Efficacy and Safety Outcomes in the Japanese Cohort (Assessed on a Time-to-First Event Basis) (Randomized Set)
| Outcomea |
Dabigatran (n=294) |
Aspirin (n=300) |
Hazard ratio,
(95% confidence
interval)b |
Patients with
event, n (%) |
Event rate,
%/year |
Patients with
event, n (%) |
Event rate,
%/year |
| Efficacy outcomes |
| Recurrent stroke |
20 (6.8) |
4.3 |
38 (12.7) |
8.3 |
0.55 (0.32–0.94) |
| Ischemic stroke |
20 (6.8) |
4.3 |
37 (12.3) |
8.0 |
0.56 (0.33–0.97) |
Non-fatal stroke, non-fatal myocardial
infarction, or cardiovascular death |
24 (8.2) |
5.2 |
39 (13.0) |
8.5 |
0.64 (0.39–1.07) |
| Disabling strokec |
2 (0.7) |
0.4 |
8 (2.7) |
1.6 |
0.25 (0.05–1.17) |
| Death from any cause |
8 (2.7) |
1.7 |
2 (0.7) |
0.4 |
4.24 (0.89–20.19) |
| Safety outcomes |
| Major bleeding |
12 (4.1) |
2.5 |
17 (5.7) |
3.5 |
0.72 (0.34–1.52) |
| Major intracranial hemorrhage |
5 (1.7) |
1.0 |
9 (3.0) |
1.8 |
0.55 (0.18–1.65) |
| Life-threatening bleed |
6 (2.0) |
1.3 |
13 (4.3) |
2.7 |
0.46 (0.17–1.21) |
| Fatal bleed |
0 |
0 |
0 |
0 |
Not evaluable |
| Any bleedd |
103 (35.0) |
28.5 |
95 (31.7) |
25.2 |
1.14 (0.86–1.51) |
| Gastrointestinal bleedd |
13 (4.4) |
2.8 |
20 (6.7) |
4.2 |
0.69 (0.34–1.38) |
aAll outcomes were confirmed by adjudication unless otherwise indicated. bCovariates in the Cox-proportional model were age (< or ≥75 years), renal impairment (creatinine clearance < or ≥50 mL/min), and stroke or transient ischemic attack prior to index stroke (yes or no). cDisabling stroke was defined as an adjudicated stroke with investigator-determined modified Rankin Scale score ≥4 at 3 months post stroke. dAny bleeds and gastrointestinal bleeds were determined by the investigator.
Table 3
shows secondary outcomes. Ischemic stroke occurred less often in the dabigatran than the aspirin group (HR, 0.56; 95% CI, 0.33–0.97). Eight patients (2.7%; 1.7%/year) died from any cause in the dabigatran group, including 3 cardiovascular deaths; 2 patients (0.7%; 0.4%/year) died from any cause in the aspirin group, including 1 cardiovascular death (HR, 4.24; 95% CI, 0.89–20.19) (Table 4).
Table 4.
Causes of Death in the Japanese Cohort
| Cause of death |
Number (%) of patients |
| Dabigatran (n=294) |
Aspirin (n=300) |
| Total |
8 (2.7) |
2 (0.7) |
| Cardiovascular |
3 (1.0) |
1 (0.3) |
| Ischemic heart disease |
2a |
0 |
| Suspected brain stem infarction |
1 |
0 |
| Pontine hemorrhage |
0 |
1 |
| Non-cardiovascular |
5 (1.7) |
1 (0.3) |
| Acute renal failure |
1 |
0 |
| Worsening of interstitial pneumonia |
1 |
0 |
| Near-drowning |
1a |
0 |
| Pancreatic carcinoma |
1 |
0 |
| Pneumonia |
0 |
1 |
| Suspected hemorrhagic gastric ulcer |
1a |
0 |
aDeath from ischemic heart disease, near-drowning, and suspected hemorrhagic gastric ulcer occurred on treatment in 1 patient each; other events occurred off treatment.
The non-Japanese cohort showed no difference between the treatment groups in the incidence of first recurrent stroke (HR, 0.91; 95% CI, 0.74–1.14) (Table 5). The difference in the treatment effect between the Japanese and non-Japanese cohort was not statistically significant (P-interaction=0.09).
Table 5.
Efficacy and Safety Outcomes in the Non-Japanese Cohort (Assessed on a Time-to-First Event Basis) (Randomized Set)
| Outcomea |
Dabigatran (n=2,401) |
Aspirin (n=2,395) |
Hazard ratio,
(95% confidence
interval)b |
Patients with
event, n (%) |
Event rate,
%/year |
Patients with
event, n (%) |
Event rate,
%/year |
| Efficacy outcomes |
| Recurrent stroke |
157 (6.5) |
4.1 |
169 (7.1) |
4.4 |
0.91 (0.74–1.14) |
| Ischemic stroke |
152 (6.3) |
3.9 |
166 (6.9) |
4.3 |
0.90 (0.72–1.12) |
Non-fatal stroke, non-fatal myocardial
infarction, or cardiovascular death |
183 (7.6) |
4.8 |
193 (8.1) |
5.0 |
0.93 (0.76–1.14) |
| Disabling strokec |
23 (1.0) |
0.6 |
34 (1.4) |
0.9 |
0.66 (0.39–1.11) |
| Death from any cause |
48 (2.0) |
1.2 |
56 (2.3) |
1.4 |
0.83 (0.56–1.22) |
| Safety outcomes |
| Major bleeding |
65 (2.7) |
1.6 |
47 (2.0) |
1.2 |
1.36 (0.93–1.97) |
| Major intracranial hemorrhage |
27 (1.1) |
0.7 |
23 (1.0) |
0.6 |
1.14 (0.66–2.00) |
| Life-threatening bleed |
32 (1.3) |
0.8 |
32 (1.3) |
0.8 |
0.98 (0.60–1.59) |
| Fatal bleed |
0 |
0 |
3 (0.1) |
0.1 |
Not evaluable |
| Any bleedd |
430 (17.9) |
12.2 |
345 (14.4) |
9.5 |
1.27 (1.10–1.46) |
| Gastrointestinal bleedd |
98 (4.1) |
2.5 |
53 (2.2) |
1.3 |
1.84 (1.32–2.58) |
aAll outcomes were confirmed by adjudication unless otherwise indicated. bCovariates in the Cox-proportional model were age (< or ≥75 years), renal impairment (creatinine clearance < or ≥50 mL/min), and stroke or transient ischemic attack prior to index stroke (yes or no). cDisabling stroke was defined as an adjudicated stroke with investigator-determined modified Rankin Scale score ≥4 at 3 months post stroke. dAny bleeds and gastrointestinal bleeds were determined by the investigator.
Tests for potential treatment by subgroup interactions in the Japanese cohort indicated that the treatment effect on the primary outcome was consistent across pre-specified subgroups of Japanese patients (Figure 3).
Safety Outcomes
The incidence of major bleeding in the Japanese cohort was similar in the 2 treatment arms: 12 dabigatran patients (4.1%; 2.5%/year) and 17 aspirin patients (5.7%; 3.5%/year) (HR, 0.72; 95% CI, 0.34–1.52) (Table 3, Figure 2). In contrast, major bleeding was more common in the dabigatran than the aspirin group in the non-Japanese cohort: dabigatran 2.7% (1.6%/year) vs. aspirin 2.0% (1.2%/year) (HR, 1.36; 95% CI, 0.93–1.97) (Table 5). The difference in the treatment effect between the Japanese and non-Japanese cohort was not statistically significant (P-interaction=0.16). In the Japanese cohort, major intracranial hemorrhage occurred in 5 patients (1.7%; 1.0%/year) in the dabigatran group (2 intracerebrally, 2 in a subdural space, and 1 in a subarachnoid space), and 9 (3.0%; 1.8%/year) in the aspirin group (6 intracerebrally, 2 in a subarachnoid space, and 1 in both a subarachnoid space and intracerebrally) (HR, 0.55; 95% CI, 0.18–1.65). Life-threatening bleeding occurred in 6 dabigatran patients (2.0%; 1.3%/year) and 13 aspirin patients (4.3%; 2.7%/year) (HR, 0.46; 95% CI, 0.17–1.21). There were no fatal bleeds (Table 1).
In the Japanese cohort, similar proportions of patients in both groups had any AEs (dabigatran: 82.9%; aspirin: 83.3%), serious AEs (dabigatran: 29.0%; aspirin: 31.3%), and AEs leading to discontinuation (dabigatran: 19.1%; aspirin: 19.3%) (Supplementary Table 2).
Discussion
The major new finding of this subanalysis from the RE-SPECT ESUS study was that dabigatran was potentially associated with a lower risk of recurrent stroke relative to aspirin in Japanese patients developing ESUS, whereas no statistically significant difference was shown in non-Japanese patients. In particular, the incidence of recurrent stroke was higher with aspirin in the Japanese than in the non-Japanese cohort. However, P-interaction for treatment × region did not reach statistical significance (P=0.09). The second major finding was that the risk of major bleeding was comparable for dabigatran and aspirin in Japanese ESUS patients.
The differences in results of the primary efficacy outcome between Japanese and non-Japanese patients did not seem to be due to pharmacological mechanisms. The pharmacokinetic profile of dabigatran is consistent across a broad range of different patient populations and is unaffected by ethnic origin such as Japanese vs. Caucasians;12,13
the plasma concentration of dabigatran was similar between overall participants of the Randomized Evaluation of Long Term Anticoagulant Therapy (RE-LY) and those from Japan both at the trough and 2 h after administration.14
To interpret the differences in the primary results, differences in baseline characteristics between Japanese and non-Japanese patients should be considered. The trend towards a older age of Japanese patients suggests a relatively high possibility of covert AF, although the HR for recurrent stroke was similar between patients aged 65–74 years and those of age ≥75 years in
Figure 3. The uniformly lower frequency (some significantly, some insignificantly) of vascular risk factors and comorbidities in Japanese compared with non-Japanese patients may indicate the less likely arterial-origin mechanism for index strokes. In addition, previous stroke other than the index stroke was twice as common in Japanese patients as in the non-Japanese cohort; such patients with multiple history of stroke generally have a relatively high recurrence rate, and cardioembolism might be a possible mechanism for frequent recurrence.15,16
Assessment of intracranial vessels is much better by MRI and MRA than by ultrasound. Preponderant use of MRI (T1, T2, T2*, diffusion-weighted imaging, fluid attenuation inversion recovery, etc.) for diagnosis of index strokes in Japan (99.8% in this study vs. 76.8% in the non-Japanese cohort) and MRA (92.8% vs. 41.8%) was helpful to detect intracranial artery stenosis accurately (assessed for all patients recruited in RE-SPECT ESUS as it was an exclusion criterion) and to depict small multiple infarcts accurately that were suggestive of embolic mechanism. Thus, index strokes of Japanese patients in this trial may have been more cardioembolic and less atheroembolic than for non-Japanese patients. Additionally, insertable cardiac monitors were officially approved for use in Japan for detecting AF in ESUS patients in March 2016, and entered clinical use 6 months later, behind approval in other major countries.17
Thus, the chance to identify covert AF before randomization might be somewhat reduced in Japan compared with other countries.
The possible reason for the presumed high frequency of cardioembolism as a covert cause of ESUS in Japanese patients was that many Japanese investigators tend to consider the concept of ESUS more strictly than the Cryptogenic Stroke/ESUS International Working Group, conducting all modalities of MRI/MRA for ESUS diagnosis. In Japan, when choosing candidates suitable for insertable cardiac monitors, the clinical guide for diagnosing ESUS lists the following 6 inclusion criteria: (1) stroke detected by MRI that is not a single small-artery lesion; (2) absence of extracranial/intracranial atherosclerosis causing ≥50% luminal stenosis in arteries supplying the ischemic area; (3) no major-risk cardioembolic source of embolism; (4) no definite diagnosis of paradoxical embolic stroke; (5) no definite diagnosis of aortogenic embolic stroke; and (6) no other specific cause of stroke identified.17
The criteria were established to prevent over-diagnosis of ESUS before inserting cardiac monitors, mainly because they are expensive. Although transesophageal echocardiography or venous duplex ultrasonography were not highly recommended for all stroke patients in the guide, Japanese physicians in high-volume stroke centers — like the sites participating in this trial — were likely to use the stricter criteria for ESUS diagnosis.
Data from the SOCRATES trial (early secondary stroke prevention after non-cardioembolic ischemic stroke) indicated twice-as-high 90-day incidence of any stroke (11.0% vs. 5.1%) and ischemic stroke (10.8% vs. 5.0%) in Asians (26% were Japanese) vs. non-Asian aspirin users.18
These observations may be partly due to a higher stroke incidence in Asians and may also reflect a poorer response to aspirin in Asians. Japanese vs. non-Japanese patients in RE-SPECT ESUS assigned to take aspirin showed similar differences in annualized incidence of any recurrent stroke (12.7% vs. 7.1%) and of ischemic stroke (12.3% vs. 6.9%). Based on these results, the similar annualized incidence of the primary efficacy outcome (6.8% vs. 6.5%), and most secondary efficacy outcomes, between Japanese and non-Japanese dabigatran users suggests that dabigatran was somewhat effective for the Japanese cohort. A reason might be that stroke patients with an aspirin-ineffective mechanism (i.e., those with potent cardioembolism) were more likely to have been included in the Japanese cohort. The safety of dabigatran was at least equivalent to that of aspirin, as shown in the main results of the global analysis,7
and was reproduced in this Japanese subanalysis.
A strength of this subanalysis is that it was pre-specified following a request from the Japanese government, although it is not expected to lead to a new indication. Another strength is that the relatively large population (594 patients) and very high follow-up completion rate (591/594; 99.5%) enabled us to perform statistically meaningful analysis of efficacy outcomes. An essential limitation was that this was a substudy of the global trial. The number of patients enrolled in the Japanese cohort was a small proportion (only ∼11%) of the total RE-SPECT ESUS population. As such, this subanalysis is not powered for either efficacy or safety outcomes, meaning results may also be due to chance.
Conclusions
The risk of recurrent stroke was lower, although the P-interaction for treatment and region did not reach statistical significance. The risk of major bleeding was similar with dabigatran compared with aspirin for Japanese ESUS patients. The present study results underscore the need for additional trials to determine the reproducibility of these findings using stricter criteria for ESUS than those used currently, and a larger trial design powered to determine efficacy and safety differences in this population, although results would be hypothesis-generating.
Acknowledgments
Medical writing support was provided by Keith Day, PhD, from Parexel. The authors wish to thank Kimiko Mitani of Nippon Boehringer Ingelheim (NBI), Tokyo, for manuscript preparation support.
Sources of Funding
This study was funded by Nippon Boehringer Ingelheim (NBI).
Disclosures
The RE-SPECT ESUS trial (NCT02239120) is funded by Boehringer Ingelheim; trial Registration: ClinicalTrials.gov NCT02239120; Japic CTI-152868.
K.T. reports receiving honoraria from Bayer Yakuhin, Nippon Boehringer Ingelheim (NBI), Bristol-Myers Squibb, and Daiichi-Sankyo. S.U. reports receiving grant support, honoraria, advisory board fees, and lecture fees from Amgen, Astellas, AstraZeneca, Bayer, NBI, Bristol-Myers Squibb, Daiichi Sankyo, Dainippon Sumitomo, Mitsubishi Tanabe, Otsuka, Sanofi, Shionogi, and Takeda. Y.H. has no conflicts to disclose. T.K. reports receiving lecture fees from NBI. T.M. discloses honoraria from Bayer Yakuhin Ltd. K.K. reports receiving lecture fees from Amgen, Astellas, Bayer, NBI, Bristol-Myers Squibb, Daiichi Sankyo, Dainippon Sumitomo, Kowa, Mitsubishi Tanabe, Mochida, Nihon Medi-Physics, Otsuka, Pfizer, Sysmex, and Takeda. L.C., C.G., and M.B. are employees of Boehringer Ingelheim. Y.U., A.T., and K.N. are employees of NBI. H.-C.D. discloses honoraria for participation in clinical trials, contribution to advisory boards, or oral presentations, or research grants from: Abbott, Achelios, Allergan, AstraZeneca, Bayer Vital, Boehringer Ingelheim, Bristol-Myers Squibb, CoAxia, Corimmun, Covidien, Daiichi-Sankyo, D-Pharm, Fresenius, GlaxoSmithKline, Janssen-Cilag, Johnson & Johnson, Knoll, Lilly, Lundbeck, Medtronic, Merck Sharp Dohme, MindFrame, Neurobiological Technologies, Novartis, Novo Nordisk, Paion, Parke-Davis, Pfizer, Portola, Sanofi-Aventis, Schering-Plough, Servier, Solvay, St Jude, Syngis, Talecris, Thrombogenics, WebMD Global, Wyeth, and Yamanouchi.
IRB Information
The institutional review board of the National Hospital Organization Kyushu Medical Center approved this study (14C30).
Data Availability
To ensure independent interpretation of clinical study results, Boehringer Ingelheim grants all external authors access to all relevant material, including participant-level clinical study data, and relevant material as needed by them to fulfill their role and obligations as authors under the International Committee of Medical Journal Editors criteria.
Furthermore, clinical study documents (e.g., study report, study protocol, statistical analysis plan) and participant clinical study data are available to be shared after publication of the primary manuscript in a peer-reviewed journal and if regulatory activities are complete and other criteria met as per the Boehringer Ingelheim Policy on Transparency and Publication of Clinical Study Data: https://trials.boehringer-ingelheim.com/transparency_policy.html. Prior to providing access, documents will be examined, and, if necessary, redacted and the data will be deidentified, to protect the personal data of study participants and personnel, and to respect the boundaries of the informed consent of the study participants. Clinical Study Reports and Related Clinical Documents can be requested via this link: https://trials.boehringer-ingelheim.com/trial_results/clinical_submission_documents.html.
All such requests will be governed by a Document Sharing Agreement. Bona fide, qualified scientific and medical researchers may request access to deidentified, analyzable participant clinical study data with corresponding documentation describing the structure and content of the datasets. Upon approval, and governed by a Data Sharing Agreement, data are shared in a secured data-access system for a limited period of 1 year, which may be extended upon request. Researchers should use https://vivli.org/ to request access to study data.
Supplementary Files
Please find supplementary file(s);
http://dx.doi.org/10.1253/circj.CJ-20-0563
References
- 1.
Toyoda K, Inoue M, Koga M. Small but steady steps in stroke medicine in Japan. J Am Heart Assoc 2019; 8: e013306.
- 2.
Ntaios G, Papavasileiou V, Milionis H, Makaritsis K, Manios E, Spengos K, et al. Embolic strokes of undetermined source in the Athens stroke registry: A descriptive analysis. Stroke 2015; 46: 176–181.
- 3.
Hart RG, Diener HC, Coutts SB, Easton JD, Granger CB, O’Donnell MJ, et al. Embolic strokes of undetermined source: The case for a new clinical construct. Lancet Neurol 2014; 13: 429–438.
- 4.
Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI, Ezekowitz MD, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014; 45: 2160–2236.
- 5.
Lansberg MG, O’Donnell MJ, Khatri P, Lang ES, Nguyen-Huynh MN, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e601S–e636S.
- 6.
Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: A meta-analysis of randomised trials. Lancet 2014; 383: 955–962.
- 7.
Diener HC, Sacco RL, Easton JD, Granger CB, Bernstein MD, Uchiyama S, et al. Dabigatran for prevention of stroke after embolic stroke of undetermined source. N Engl J Med 2019; 380: 1906–1917.
- 8.
Hart RG, Sharma M, Mundl H, Kasner SE, Bangdiwala SI, Berkowitz SD, et al. Rivaroxaban for stroke prevention after embolic stroke of undetermined source. N Engl J Med 2018; 378: 2191–2201.
- 9.
Diener HC, Easton JD, Granger CB, Cronin L, Duffy C, Cotton D, et al. Design of Randomized, double-blind, Evaluation in secondary Stroke Prevention comparing the EfficaCy and safety of the oral Thrombin inhibitor dabigatran etexilate vs. acetylsalicylic acid in patients with Embolic Stroke of Undetermined Source (RE-SPECT ESUS). Int J Stroke 2015; 10: 1309–1312.
- 10.
Healey JS, Connolly SJ, Gold MR, Israel CW, Van Gelder IC, Capucci A, et al. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med 2012; 366: 120–129.
- 11.
Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the Scientific Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3: 692–694.
- 12.
Stangier J, Clemens A. Pharmacology, pharmacokinetics, and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor. Clin Appl Thromb Hemost 2009; 15(Suppl 1): 9S–16S.
- 13.
Härtter S, Yamamura N, Stangier J, Reilly PA, Clemens A. Pharmacokinetics and pharmacodynamics in Japanese and Caucasian subjects after oral administration of dabigatran etexilate. Thromb Haemost 2012; 107: 260–269.
- 14.
Hori M, Connolly SJ, Ezekowitz MD, Reilly PA, Yusuf S, Wallentin L; RE-LY Investigators. Efficacy and safety of dabigatran vs. warfarin in patients with atrial fibrillation: Sub-analysis in Japanese population in RE-LY trial. Circ J 2011; 75: 800–805.
- 15.
Hata J, Tanizaki Y, Kiyohara Y, Kato I, Kubo M, Tanaka K, et al. Ten year recurrence after first ever stroke in a Japanese community: The Hisayama study. J Neurol Neurosurg Psychiatry 2005; 76: 368–372.
- 16.
Kolominsky-Rabas PL, Weber M, Gefeller O, Neundoerfer B, Heuschmann PU. Epidemiology of ischemic stroke subtypes according to TOAST criteria: Incidence, recurrence, and long-term survival in ischemic stroke subtypes: A population-based study. Stroke 2001; 32: 2735–2740.
- 17.
Toyoda K, Okumura K, Hashimoto Y, Ikeda T, Komatsu T, Hirano T, et al. Identification of covert atrial fibrillation in cryptogenic ischemic stroke: Current clinical practice in Japan. J Stroke Cerebrovasc Dis 2016; 25: 1829–1837.
- 18.
Johnston SC, Amarenco P, Albers GW, Denison H, Easton JD, Evans SR, et al. Ticagrelor versus aspirin in acute stroke or transient ischemic attack. N Engl J Med 2016; 375: 35–43.
