Magnetic Resonance Imaging-Guided Intravenous Thrombolysis in Cardioembolic Stroke Patients With Unknown Time of Onset　― Subanalysis of the THAWS Randomized Control Trial ―

Abstract

Background: We investigated the clinical effect of intravenous thrombolysis using a magnetic resonance imaging (MRI)-guided approach in cardioembolic stroke (CE) patients with unknown time of onset.

Methods and Results: This subanalysis of the THAWS trial assessed the efficacy and safety of alteplase 0.6 mg/kg in CE patients with unknown time of onset and showing diffusion-weighted imaging–fluid-attenuated inversion recovery mismatch. Patients were classified as CE and non-CE using the SSS-TOAST classification system during the acute period. The efficacy outcome was a modified Rankin Scale score of 0–1 at 90 days. In all, 126 patients from the THAWS trial were included in this study, of whom 45 (35.7%) were diagnosed with CE. In the CE group, a favorable outcome was numerically more frequent in the alteplase than control group (52% vs. 35%; adjusted odds ratio [aOR] 2.25; 95% confidence interval [CI] 0.50–9.99). However, in the non-CE group, favorable outcomes were comparable between the alteplase and control groups (44% vs. 55%, respectively; aOR 0.39; 95% CI 0.12–1.21). Treatment-by-cohort interaction for a favorable outcome was modestly significant between the CE and non-CE groups (P=0.069). In the CE group, no patients experienced symptomatic intracranial hemorrhage (ICH) or parenchymal hematoma Type II following thrombolysis.

Conclusions: When an MRI-guided approach is used, CE patients with unknown time of onset appear to be suitable candidates for thrombolysis.

Acute ischemic stroke (AIS) is a serious condition necessitating immediate and emergency medical attention. Thrombolytic therapy with intravenous alteplase has been the first-line therapy for patients with AIS within a 4.5-h window after the onset of symptoms.¹ Moreover, the Magnetic Resonance Imaging (MRI)-Guided Thrombolysis for Stroke with Unknown Time of Onset (WAKE-UP) trial,² using MRI guidance, has demonstrated the efficacy of alteplase in treating AIS patients with unknown onset time. However, the Thrombolysis With Alteplase at 0.6 mg/kg for Stroke With Unknown Time of Onset (THAWS) trial,³ conducted in Japan using a low dose (0.6 mg/kg) of alteplase, yielded dissimilar findings compared with the WAKE-UP trial. Nonetheless, a recent meta-analysis encompassing individual patient data derived from several trials, collectively known as the Evaluation of unknown Onset Stroke thrombolysis trials (EOS), unveiled that notwithstanding an increased risk of symptomatic intracranial hemorrhage, the administration of alteplase conferred a net benefit in functional outcomes.⁴

Editorial p 388

Cardioembolic stroke (CE) is the most disabling form of AIS,⁵ where atrial fibrillation (AF) emerges as a prominent antecedent of CE.⁶ Nonetheless, the effectiveness of intravenous alteplase when used for CE management remains controversial, although it is apparent that the different AIS subtypes may have a considerable effect on the therapeutic potency of thrombolysis.

Aim

To fill this gap in knowledge regarding the effectiveness of thrombolysis for CE, a subanalysis of the THAWS trial was conducted to evaluate how the diagnosis of CE affected the effectiveness of administering alteplase 0.6 mg/kg in patients with AIS with unknown onset time.

Methods

We performed a subgroup analysis using the dataset of the THAWS trial, which was an investigator-initiated, open-label, blinded-end point evaluation multicenter randomized controlled trial (University Hospital Medical Information Network [UMIN] Clinical Trials Registry ID: UMIN000011630). Full details of the trial design have been reported elsewhere.^3,7,8 Briefly, the efficacy and safety of alteplase 0.6 mg/kg was tested in patients with AIS with unknown time of onset and showing diffusion-weighted imaging (DWI)–fluid-attenuated inversion recovery mismatch. The trial was approved by the local ethics committee or institutional review board at each participating center (R19046-3, issued by National Cerebral and Cardiovascular Center). Patients or their relatives provided written informed consent according to the declaration of Helsinki and ethical regulations.

Randomization and Treatment

Patients were randomly assigned in a 1 : 1 ratio to receive either alteplase 0.6 mg/kg (alteplase group) or standard medical treatment (control group), based on a minimization scheme with stratification by the severity of symptoms assessed using the National Institutes of Health Stroke Scale (NIHSS) score (≤11 or >11). Immediately after randomization, patients in the alteplase group were administered alteplase 0.6 mg/kg within 4.5 h of symptom recognition, whereas patients in the control group received the standard medical treatment using antithrombotic drugs. The alteplase group was prohibited from using antithrombotic drugs during the initial 25 h. Treatment was initiated as soon as possible, within 60 min after MRI examination.

Clinical and Imaging Assessments

Certified neurologists or neurosurgeons performed clinical assessments, including the NIHSS sore at baseline. Outcomes at 90 days were assessed in a blinded manner by independent and certified examiners without information about treatment allocation. According to the classification system of the Stop Stroke Study–Trial of Org 10172 in Acute Stroke Treatment (SSS-TOAST),⁹ stroke subtypes were classified into 5 groups: large artery atherosclerosis, CE, small vessel occlusion, stroke of other determined etiology, and stroke of undetermined etiology. CE was diagnosed by certified neurologists or neurosurgeons at each institution before hospital discharge, using the presence of AF and other high-risk cardiac sources,⁴ during admission to an acute care hospital. According to subtype classification, patients were dichotomized into CE and non-CE groups. We evaluated the modified HAS-BLED score,¹⁰ which assigns 1 point for each of the following factors: systolic blood pressure ≥160 mmHg, abnormal renal function, abnormal liver function, history of stroke, bleeding risk, age >65 years, medical history of antiplatelet use, and alcohol abuse.

Outcome Measures

The primary efficacy outcome was defined as a modified Rankin scale (mRS) score of 0–1 at 90 days after stroke onset. Secondary efficacy outcomes were an mRS score of 0–2 at 90 days after stroke onset and a category shift in mRS score at 90 days. Safety outcomes were any intracranial hemorrhage (ICH), parenchymal hematoma (PH) Type II, and symptomatic ICH at 22–36 h. The definition of symptomatic ICH was an increase in the NIHSS score ≥4 from baseline and PH Type II on MRI 22–36 h after treatment initiation.

Statistical Analysis

Data are presented as the median with interquartile range (IQR) or as numbers and percentages. Efficacy analyses were performed on the intention-to-treat population, and safety analyses were conducted with data from treated patients. The treatment groups were compared using the Wilcoxon rank-sum test for continuous variables and the χ² test or Fisher’s exact test for categorical variables. The effects of alteplase on each outcome were compared between the assigned treatment groups (alteplase and control) in patients who were diagnosed with CE and those who were not, separately. In each group, crude analysis and multivariable analysis adjusted for age, sex, DWI–Alberta Stroke Program Early CT Score (ASPECTS), and baseline NIHSS score were performed to determine the difference in frequencies of outcomes between the alteplase and control groups. The analysis of category shift in mRS was performed using the assumption-free ordinal analysis on the full range (0–6) of the mRS, with adjustment for age, sex, DWI-ASPECTS, and baseline NIHSS score. For outcomes, the interaction between the assigned treatment group and diagnosis of CE was assessed. We considered P<0.15 statistically significant for the assessment of the treatment-by-CE interaction. We also performed a univariate analysis to evaluate the association between the modified HAS-BLED score and safety outcomes. For the primary and secondary outcomes, two-tailed P value <0.05 was used to indicate statistical significance. For exploratory purposes, multiplicity is not considered in secondary analysis. Statistical analyses were performed using JMP version 12 (SAS Institute, Cary, NC, USA) and STATA version 16 (StataCorp LP, College Station, TX, USA).

Results

Of 131 patients undergoing randomization in the THAWS trial from May 2014 to July 2018, 126 (median age 77 years, 53 women) were included in the present study, with 90-day follow-up assessment within the allowed schedule. These patients were identical to the cohort for the primary outcome analysis in the main article.³ Of these patients, 45 (35.7%) were diagnosed with CE, and this group had significantly more AF, cardiac disease, and vessel occlusion on baseline magnetic resonance angiography, less wake-up stroke, a lower DWI-ASPECTS, and a higher NIHSS score on admission (Table 1). Of note, 2 patients in the non-CE group had a prior medical history of AF; 1 of them was diagnosed as large artery atherosclerosis, whereas the other was diagnosed with stroke of undetermined etiology due to their early death before a detailed examination.

Table 1.

Baseline Characteristics of Patients With or Without Cardioembolic Stroke

Variables	CE (n=45)	Non-CE (n=81)	P value
Age (years)	77.2±13.1	72.7±13.1	0.069
Male sex	22 (48.8)	51 (62.9)	0.125
Medical history
Hypertension	33 (73.3)	53 (65.4)	0.361
Diabetes	10 (22.2)	15 (18.5)	0.617
Dyslipidemia	15 (33.3)	30 (37.0)	0.677
Atrial fibrillation	28 (62.2)	2 (2.4)	<0.0001
Cardiac disease	34 (75.5)	12 (14.8)	<0.0001
History of ischemic stroke/TIA	9 (20.0)	11 (13.5)	0.344
Prior use of antihypertensive medication	31 (68.8)	39 (48.1)	0.0016
Prior use of antithrombotic medication	21 (46.6)	19 (23.4)	0.506
Atrial fibrillation at admission	31 (68.8)	1 (1.2)	<0.0001
Premorbid modified Rankin Scale score	0 [0–0]	0 [0–0]	0.147
Recognition at awaking (wake-up stroke)	20 (44.4)	69 (85.1)	<0.0001
Initial NIHSS score	11 [5.5–16]	6 [4–9]	0.001
Baseline DWI-ASPECTS	8 [7–9]	9 [8.5–10]	0.0003
Negative DWI at baseline	6 (13.3)	15 (18.5)	0.454
Vessel occlusion on baseline MRA	22 (48.8)	17 (20.9)	0.0012
LKW to symptom recognition (min)	420 [345–579]	420 [325–540]	0.340
Symptom recognition to randomization (h)	3.0 [2.3–4.1]	3.0 [2.3–3.9]	0.652
LKW to randomization (h)	10.7 [8.4–14.7]	10.5 [7.7–12.4]	0.399

Unless indicated otherwise, data are given as the mean±SD, median [interquartile range], or n (%). CE, cardioembolic stroke; DWI, diffusion-weighted imaging; DWI-ASPECTS, Alberta Stroke Program Early CT Score on DWI; LKW, last-known well; MRA, magnetic resonance angiography; NIHSS, National Institutes of Health Stroke Scale; TIA, transient ischemic attack.

Clinical outcomes are presented in Table 2. A favorable outcome (mRS score 0–1) in the CE group was numerically more frequent in the alteplase than control group (52% vs. 35%, respectively; adjusted odds ratio [aOR] 2.25; 95% confidence interval [CI] 0.50–9.99; Figure). However, in the non-CE group, favorable outcomes were comparable between the alteplase and control groups (44% vs. 55%, respectively; aOR 0.39; 95% CI 0.12–1.21). The treatment-by-cohort interaction for a favorable outcome between the CE and non-CE groups showed modest significance (P=0.069). A similar level of significance was observed for the treatment-by-cohort interaction in achieving an mRS score of 0–2 (P=0.059; Table 2). The treatment-by-cohort interaction for a category shift in mRS score at 90 days, adjusted for age, sex, DWI-ASPECTS, and baseline NIHSS score, did not reach statistical significance (P=0.175; Table 3).

Table 2.

Efficacy Outcomes

mRS score at 90 days	Alteplase groupA (n=68)	Control groupA (n=58)	Crude OR (95% CI)	P value	P value for interaction	Adjusted ORB (95% CI)	P value	P value for interaction
0–1
CE	13/25 (52)	7/20 (35)	2.01 (0.60–6.99)	0.25	0.133	2.25 (0.50–9.99)	0.412	0.069
Non-CE	19/43 (44)	21/38 (55)	0.64 (0.26–1.54)	0.32		0.39 (0.12–1.21)	0.10
0–2
CE	16/25 (64)	9/20 (45)	2.17 (0.65–7.24)	0.20	0.087	2.63 (0.53–12.9)	0.235	0.059
Non-CE	24/43 (55)	26/38 (68)	0.58 (0.23–1.45)	0.24		0.36 (0.11–1.12)	0.08

^AData show n/total N (%). ^BAdjusted for age, sex, Alberta Stroke Program Early CT Score on diffusion-weighted imaging at admission, and baseline National Institutes of Health Stroke Scale score. CE, cardioembolic stroke; CI, confidence interval; mRS, modified Rankin Scale; OR, odds ratio.

Figure.

Distribution of modified Rankin Scale (mRS) scores 90 days after stroke onset in the alteplase and control groups in patients with or without cardioembolic stroke (CE). Values within the graphs show the number of patients; percentages are provided along the x-axis.

Table 3.

Categorical Shift in Modified Rankin Scale Score at 90 Days

	Median (IQR) mRS score		Effect size (95% CI)		P value for interaction
	Alteplase group (n=68)	Control group (n=58)	Crude OR	Adjusted ORA
CE (n=45)	1 (1–3)	3 (1–4.5)	0.58 (0.20–1.69)	0.57 (0.19–1,76)	0.175
Non-CE (n=81)	2 (1–4)	1 (0–3)	1.54 (0.70–3.36)	1.50 (0.68–3.33)

^AAdjusted for age, sex, Alberta Stroke Program Early CT Score on diffusion-weighted imaging at admission, and baseline National Institutes of Health Stroke Scale score. IQR, interquartile range. Other abbreviations as in Table 2.

Safety outcomes are presented in Table 4. In the non-CE group, any ICH was more frequently observed in the alteplase than control group (20% vs 5.4%, respectively; OR 4.5; 95% CI 1.06–30.92; P=0.04). However, in the CE group, there was no significant difference between the alteplase and control groups in the incidence of any ICH (36% vs 30%, respectively; OR 1.31; 95% CI 0.37–4.79; P=0.67). The treatment-by-cohort interaction was also not significant (P=0.19). No patients in the CE group experienced symptomatic ICH or PH Type II at 22–36 h following thrombolysis. In both groups, symptomatic ICH and any cause of death (mRS 6) at 90 days did not differ significantly between the allocated treatment groups. Two patients in the control group in the CE group and 2 patients in the alteplase group in the non-CE group experienced PH Type II, which was significant in the treatment-by-cohort interaction (P=0.01). The median modified HAS-BLED score was 2 (IQR 1–2) in both the alteplase and control groups for patients with CE. In patients without CE, the median modified HAS-BLED score was also 2 (IQR 1–2). There was no significant association between the HAS-BLED score and the occurrence of any ICH, symptomatic ICH, PH Type II or mRS 6 at 90 days in both the CE and non-CE groups.

Table 4.

Safety Outcomes

	Alteplase groupA (n=69)	Control groupA (n=57)	OR (95% CI)	P value	P value for interaction
Any ICH at 36 h
CE	9/25 (36)	6/20 (30)	1.31 (0.37–4.79)	0.67	0.19
Non-CE	9/44 (20)	2/37 (5.4)	4.50 (1.06–30.92)	0.04
Symptomatic ICH at 36 h
CE	0/25 (0)	0/20 (0)	–	–	0.98
Non-CE	1/44 (2)	0/37 (0)	–	1
PH Type 2 at 36 h
CE	0/25 (0)	2/20 (10)	–	0.06	0.01
Non-CE	2/44 (4)	0/37 (0)	–	0.11
mRS 6 at 90 days
CE	1/25 (4)	0/20 (0)	–	1	0.16
Non-CE	1/44 (2)	2/37 (5)	0.40 (0.01–4.41)	0.45

^AData show n/total N (%). ICH, intracranial hemorrhage; PH, parenchymal hematoma. Other abbreviations as in Table 2.

Discussion

The effectiveness and safety of thrombolysis for CE patients with unknown time of onset was assessed. Our analysis revealed a significant treatment-by-cohort interaction for a favorable outcome and no increases in safety concerns between patients in the CE and non-CE groups. These findings indicate that CE patients with an unknown time of onset are suitable candidates for MRI-guided thrombolysis.

The efficacy of alteplase for CE has been a topic of debate. A recent meta-analysis indicated that intravenous thrombolysis for patients with AF was more likely to result in poor outcomes.¹¹ Conversely, Yang et al retrospectively reported the efficacy of alteplase for patients with AF in an extended time window using multimodal computed tomography,¹² which is similar to the use of image-guided thrombolysis in the present study. Our randomized study, which confirmed DWI–FLAIR mismatch in all cases, provides stronger evidence that CE patients with an unknown time of onset are suitable candidates for MRI-guided intravenous thrombolysis.

Our study also suggests that low-dose alteplase is effective in treating CE. The dose of alteplase in Japan is lower (0.6 mg/kg), as determined by the results of the Japan Alteplase Clinical Trial,¹³ than standard therapy (0.9 mg/kg) used in other countries. However, low-dose alteplase failed to show efficacy against standard-dose alteplase outside Japan.¹⁴ Kimura et al reported that AF was a factor in recanalization failure,¹⁵ and a previous study reported that low-dose alteplase may be responsible for this failure.¹² Despite these concerns, our findings indicate that MRI-guided thrombolysis with alteplase 0.6 mg/kg is effective in CE patients with an unknown time of onset.

Surprisingly, our study showed that the CE group had a comparable or even numerically lower mRS score than the non-CE group, despite having a more severe NIHSS score and lower DWI-ASPECTS, indicating a benefit from MRI-guided thrombolysis. Several factors could explain this result. First, the alteplase group was prohibited from using any antithrombotic drugs within 25 h, making it difficult to reinforce treatment for the non-CE patients in the event of symptom deterioration. Delay in the start of dual antiplatelet therapy, which has been shown to be effective for acute non-CE ischemic stroke, could lead to poor outcomes in atherosclerotic stroke.¹⁶ Second, the CE group had nearly twice as much vessel occlusion at baseline as the non-CE group, making them good candidates for MRI-guided thrombolysis. Although the efficacy of alteplase for AF is limited due to its high incidence of large vessel occlusion,¹⁵ our study excluded patients eligible for mechanical thrombectomy and selected patients with intermediate severity and ineligible for mechanical thrombectomy; these patients may be good candidates for MRI-guided thrombolysis.¹⁷

We also found that the assessment of bleeding risk using the HAS-BLED score¹⁸ did not show any association with the occurrence of ICH at 22–36 h or mortality at 90 days in both the CE and non-CE groups. This lack of association may be attributed to our exclusion of patients with a large infarct, as determined by a DWI-ASPECTS of <5 with MRI guidance.¹⁹ This exclusion criterion likely contributed to maintaining an acceptable safety profile not only in the non-CE group, but also in the CE group.

Our study has several limitations. First, the number of patients was small because the THAWS trial was terminated without enrolling the planned number of patients. Second, as described in the previous report,³ the THAWS trial was an open-treatment design and used alteplase 0.6 mg/kg. Third, the non-CE group may include patients with paroxysmal AF, which was not verified during the admission period. Finally, it is important to acknowledge the potential for overlooking cryptogenic causes due to variations in diagnostic processes among hospitals. Diagnostic protocols can differ, with some hospitals using methods such as transesophageal echocardiography²⁰ and contrast enhanced computed tomography.²¹ This variability may have led us to miss potential sources of embolic stroke, such as aortic plaque, right-to-left shunt, and malignancies.²² In fact, patients in both the CE and non-CE groups exhibited baseline vessel occlusion (48.8% and 20.9%, respectively), which could potentially be attributed to cryptogenic sources unrelated to cardiogenic factors.

Conclusions

In summary, our data support the use of MRI-guided alteplase for CE patients with an unknown time of onset. Although patients with CE and AF are associated with severe stroke, these conditions may be good prognostic factors following MRI-guided intravenous thrombolysis.

Acknowledgments

We thank all patients, investigators, and medical staff involved in the THAWS trial.

Sources of Funding

This study was supported, in part, by funding from the Japan Agency for Medical Research and Development (Grant no. 23lk0221171 h0001).

Disclosures

K.A., J.A., M.F.-D., K. Miwa, H.Y., N.Y., and S.Y. have nothing to declare. R.D. reports honoraria from Daiichi-Sankyo, Pfizer/BMS, Eisai, Medtronic, Cerenovous, Stryker, Abbott, and Biotronik, outside the submitted work. M. Ihara reports lecturer fees from Otsuka, and grant support from Panasonic, GE Precision Healthcare, Kyocera Corporation, Towa Pharmaceutical, and Pharma Foods International. M. Inoue reports lecture fees from Daiichi Sankyo, Bayer, Nippon Boehringer Ingelheim, and Bristol Myers Squibb. K.K. reports honoraria from Daiichi-Sankyo and research support from Daiichi-Sankyo, Pfizer, Medtronic, Eizai, and Boehringer Ingelheim, all outside the submitted work. T.K. reports honoraria from Daiichi-Sankyo and research support from Daiichi-Sankyo, Takeda, Chugai, and Mitsubishi Tanabe, all outside the submitted work. T.K. is also a member of Circulation Journal’s Editorial Team. M.K. reports honoraria from Bayer Yakuhin, Daiichi-Sankyo, Mitsubishi Tanabe Pharma Corporation, and Pfizer/BMS, and research support from Daiichi-Sankyo and Nippon Boehringer Ingelheim, all outside the submitted work. K. Minematsu reports honoraria from Bayer Yakuhin and Pfizer outside the submitted work. M.S. reports honoraria from Idorsia Pharmaceuticals, Fujifilm Medical, Eizai, and MediPhysics, and research support from Idorsia Pharmaceuticals and Fujifilm Medical, all outside the submitted work. K.T. reports honoraria from Daiichi-Sankyo, Otsuka, Bayer Yakuhin, Bristol-Myers-Squibb, and Novartis, outside the submitted work.

IRB Information

The THAWS trial was approved by the local ethics committee or institutional review board at each participating center (R19046-3, issued by National Cerebral and Cardiovascular Center). Patients or their relatives provided written informed consent according to ethical regulations.

Data Availability

The deidentified participant data, including patient information and study protocol, are available from the corresponding author as CSV or Excel files via email, upon reasonable request.

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