Stroke
Magnetic Resonance Imaging-Guided Intravenous Thrombolysis for Unknown Onset Cardiogenic Stroke
2024 Volume 88 Issue 3 Pages 388-389
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2024 Volume 88 Issue 3 Pages 388-389
Stroke is increasingly recognized as a cause of mortality, morbidity, and disability in the aging society of Japan.1 Acute ischemic stroke (AIS) is a highly urgent condition, and treatment delay directly contributes to serious neurological dysfunction. In 1995, the efficacy of alteplase 0.9 mg/kg for ischemic stroke within 3 h of onset was demonstrated,2 and following that successful therapeutic strategy, Hacke et al examined whether the treatable duration could be extended up to 6 h after stroke onset.3–5 However, the European Cooperative Acute Stroke Study (ECASS) and ECASS II demonstrated no efficacy of alteplase in patients with stroke within 6 h of onset,3,4 although ECASS III demonstrated the effect of alteplase within 4.5 h after stroke onset.5
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Similarly, the efficacy of thrombectomy for AIS is well established, and demonstrated to improve neurological outcomes within 24 h of stroke onset.6 However, despite it having a longer indication time and being a highly effective therapeutic alternative for patients with stroke, the number of institutions that provide thrombectomy is limited in Japan. Therefore, the accumulation of evidence regarding the effect of alteplase as an alternative is clinically important to improve neurological outcomes in patients with AIS.
Several studies have demonstrated that ischemic changes on diffusion-weighted magnetic resonance imaging (MRI) of the head are likely to occur within 4.5 h of onset if they are not evident on fluid-attenuated inversion recovery (FLAIR) images (positive diffusion-weighted imaging (DWI)/FLAIR mismatch, Figure). This imaging-guided therapy is clinically important for patients with unknown stroke onset time. In the WAKE-UP trial, which evaluated the effect of alteplase administration within 4.5 h of stroke onset in patients with unknown onset and positive DWI/FLAIR mismatch, significantly more patients in the alteplase group had a good neurological outcome defined as modified Rankin Scale (mRS) 0–1 compared with the placebo group.7 In contrast, the Japanese THAWS trial reported by Koga et al8 could not demonstrate the efficacy of alteplase treatment in patients with unknown onset and positive DWI/FLAIR mismatch but the trial excluded patients with DWI-ASPECTS 9–10 and very small infarct size. The analysis showed that significantly more patients in the alteplase group had better outcomes at 90 days than those in the placebo group.8
Graphical summary of subanalysis from the THAWS trial. CE, cardioembolic stroke; DWI, diffusion-weighted imaging; FLAIR, fluid-attenuated inversion recovery; ICH, intracerebral hemorrhage; mRS, modified Rankin Scale. Adapted with permission from Yamazaki N, et al.9
In this issue of the Journal, Yamazaki et al9 report a subanalysis of the THAWS trial to examine the effectiveness and safety of thrombolysis in patients with AIS and cardioembolic stroke (CE) with unknown time of onset, especially focusing on brain MRI-guided thrombolysis. A total of 126 patients (median age: 77 years; 53 women) who were randomly assigned to receive 0.6 mg/kg alteplase (alteplase group) or standard medical therapy (control group) were categorized into CE or non-CE groups (Figure). The investigators found that a good neurological prognosis, defined as mRS of 0 or 1, was comparable between the 2 treatment groups in the non-CE group (44% vs. 55%), whereas in the CE group, there were more patients in the alteplase group than in the control group (52% vs. 35%). In terms of safety, intracerebral hemorrhage (ICH) was significantly more frequent in the non-CE group than in the control group (20% vs. 5.4%, P=0.04), whereas no significant difference was observed in the CE group (36% vs. 30%, P=0.67).
Similarly, Yang, et al demonstrated the efficacy of alteplase in patients with atrial fibrillation (AF).10 Although these studies showed consistent results, a recent study reported that intravenous thrombolysis exhibited increased risk of symptomatic intracranial hemorrhage in patients with AF (relative risk [RR] 2.10, 95% confidence interval [CI] 1.35–3.26).11 Recent meta-analysis showed that intravenous thrombolysis in patients with AF was associated with a significantly lower proportion of patients with mRS of 0–1 (24.1% vs. 34.5%; odds ratio [OR] 0.59, 95% CI 0.43–0.81, P<0.001), mRS of 0–2 (33.6% vs. 47.8%; OR 0.55, 95% CI 0.43–0.70, P<0.001). In addition, intracranial hemorrhage was significantly more frequent in the non-CE group than in the control group (20% vs. 5.4%; P=0.04), but no significant difference was observed in the CE group (36% vs. 30%; P=0.67). Alteplase treatment with AF was associated with significantly higher mortality rate (19.4% vs. 11.5%; OR 2.05, 95% CI 1.79–2.36, P<0.001) and a higher incidence of symptomatic intracranial hemorradge (6.4% vs. 4.1%; OR 1.60, 95% CI 1.27–2.01, P<0.001).12 Yamazaki et al reported that ICH was not significantly different in the CE group (36% vs. 30%; P=0.67) (Figure). Although the efficacy and safety of alteplase in CE remains controversial, this report by Yamazaki et al is important in supporting the efficacy of alteplase in CE.
There are several limitations to note. First, the early termination of the THAWS trial resulted in only a small number of eligible patients. Second, there may be variations in the diagnostic process for CE among institutions, which may potentially include embolic sources of stroke other than CE, such as large arterial plaques, right-to-left shunts, and malignancy. Finally, although there was no significant association between hemorrhage and anticoagulation therapy, it remains unclear whether these results can be generalized to patients with AIS caused by AF, the most common cause of embolic stroke. Further prospective studies are required to address these issues. Despite these limitations, Yamazaki et al provide evidence that patients with CE of unknown onset are appropriate candidates for MRI-guided intravenous thrombolytic therapy, which opens a new avenue for an expanded range of indication times for thrombolytic therapy in patients with stroke caused by CE.
D.F. is a member of Circulation Journal’s Editorial Team.
