Effectiveness and Limitations of Intravenous rt-PA Therapy in Patients with Mild Cerebral Infarction

Abstract

Recombinant tissue plasminogen activator (rt-PA), specifically alteplase, remains the standard treatment for acute cerebral infarction across all stroke subtypes. However, per recent randomized controlled trials (RCTs), individuals with mild cerebral infarction, medical management alone without rt-PA can yield functional outcomes comparable to those achieved with thrombolytic therapy. This has sparked ongoing debate regarding the necessity of rt-PA administration in cases of mild stroke. Nonetheless, certain individuals with mild cerebral infarction derive clear benefits from rt-PA therapy. Therefore, an individualized treatment approach should be prioritized over a uniform thrombolytic strategy in these cases. This review examines the therapeutic efficacy and limitations of rt-PA therapy for mild cerebral infarction, integrating evidence from prior clinical studies with the authors’ perspectives.

Introduction

Intravenous recombinant tissue plasminogen activator (rt-PA), specifically alteplase (IV alteplase), has been established as a first-line treatment for acute cerebral infarction across all stroke subtypes ¹⁾ . Additionally, meta-analyses have provided evidence supporting the efficacy of IV alteplase, even in individuals with mild stroke, independent of stroke severity as measured by the National Institutes of Health Stroke Scale (NIHSS) ^{2 , 3)} . However, in clinical practice, IV alteplase is frequently withheld in cases of mild cerebral infarction. Notably, studies have reported that the primary reason for withholding IV alteplase in individuals with mild stroke, despite meeting eligibility criteria, is the perceived mild nature of the stroke itself ^{4 , 5)} . In Japan, the utilization rate of IV alteplase varies by NIHSS score stage, with a reported administration rate of 2.5% for individuals with an NIHSS score of 0–4, which is substantially lower than that observed for more severe cases (NIHSS 5–10: 11.6%; NIHSS 11–16: 20.3%; NIHSS 17–22: 24.4%; NIHSS 23–25: 24.5%; NIHSS ＞26: 17.5%) ⁶⁾ . Furthermore, two recent randomized controlled trials (RCTs) failed to demonstrate the superiority of IV alteplase over medical therapy (without IV alteplase) in individuals with mild stroke ^{7 , 8)} . These findings suggest that the benefits of IV alteplase in individuals with mild stroke may be limited, particularly given the associated risk of hemorrhagic complications. Consequently, an increasing debate has emerged regarding the therapeutic value of IV alteplase in individuals with mild cerebral infarction and whether it should be administered proactively. This review examines the efficacy and limitations of IV alteplase in mild ischemic stroke, commonly defined as an NIHSS score of ≤ 5, based on evidence from existing clinical studies. Additionally, the authors provide their perspectives on its therapeutic benefits and limitations in this population.

Ⅰ.Efficacy of rt-PA Therapy in Patients with Mild Stroke: IV Alteplase versus Medical Therapy

The PRISMS (The Potential of rtPA for Ischemic Strokes with Mild Symptoms) study and the ARAMIS study are notable RCTs that evaluated the efficacy of IV alteplase compared to medical therapy without IV alteplase in individuals with mild cerebral infarction ^{7 , 8)} . The PRISMS study included individuals with acute stroke and NIHSS scores of 0 to 5, whose neurological deficits were classified as non-disabling at presentation, meaning their symptoms did not impair daily functioning or occupational activities. This study compared IV alteplase with aspirin therapy. Similarly, the ARAMIS study focused on individuals with acute stroke and NIHSS scores of 0 to 5, requiring that consciousness remained intact and each NIHSS item scored less than 1. This study compared IV alteplase with aspirin therapy as well as IV alteplase with dual antiplatelet therapy (DAPT). In both studies, no significant differences in functional outcomes were observed between the groups. However, the risk of hemorrhagic complications was higher in the IV alteplase group. While it is challenging to draw definitive conclusions based solely on these RCTs, for individuals with particularly mild ischemic stroke (NIHSS score ≤ 5), as defined in the two trials, medical management alone may yield functional outcomes comparable to those achieved with IV alteplase. Therefore, the benefit of proactively administering IV alteplase in such cases is considered to be low. The AHA/ASA guidelines do not recommend IV alteplase for individuals with mild, non-disabling stroke symptoms (NIHSS score ≤ 5), assigning it a Class Ⅲ recommendation (No Benefit) ¹⁾ . However, in clinical practice, some individuals who initially present with mild, non-disabling stroke symptoms at onset experience neurological deterioration and subsequent disability after hospitalization. In such cases, IV alteplase may be a more favorable treatment option than medical therapy alone. Even in individuals with mild cerebral infarction, it is critical to distinguish those who may benefit from IV alteplase from those who are likely to experience symptom progression despite thrombolysis. A tailored approach to treatment selection is essential to optimizing patient outcomes.

Ⅱ. Cases in which IV Alteplase should be Performed even in Mild Cases of Cerebral Infarction: with Large Vessel Occlusion (LVO)

The prevalence of LVO in mild cerebral infarction is estimated to be approximately 30% ^{9 - 12)} . Even in individuals with mild cerebral infarction, the presence of LVO is strongly associated with infarct progression and early neurological deterioration (END), both of which correlate with poor clinical outcomes ^{9 , 13 - 16)} . Therefore, when LVO is detected in an individual with mild cerebral infarction, IV alteplase should be administered proactively to facilitate vessel recanalization. A meta-analysis evaluating the efficacy of IV alteplase in individuals with mild cerebral infarction (NIHSS score ≤ 5) and LVO reported that reperfusion therapy, either IV alteplase or mechanical thrombectomy (MT), significantly improved clinical outcomes compared to conservative management without thrombolysis. Additionally, a subanalysis of the RESCUE-Japan Registry 2 found that IV alteplase was associated with superior functional outcomes in this population ^{17 , 18)} . Furthermore, a study comparing IV alteplase-mediated recanalization rates in acute ischemic strokes with intracranial occlusion between mild stroke (NIHSS score ≤ 5) and moderate/severe strokes (NIHSS score ＞5) found that the absolute rate of successful recanalization was higher in the mild stroke group. IV alteplase was also independently associated with a greater likelihood of successful recanalization in individuals with mild stroke ¹⁹⁾ . In cerebral infarction with LVO, achieving recanalization is crucial to preventing END and optimizing functional recovery. However, early recanalization with IV alteplase alone is challenging, particularly in occlusions involving the ICA and the M1 segment of the middle cerebral artery (MCA-M1) ²⁰⁾ . A study investigating vessel-specific occlusions in individuals with mild cerebral infarction (NIHSS score ≤ 5) found that the frequency of non-hemorrhagic END was higher in those with ICA occlusion. Additionally, even with IV alteplase administration, these individuals had a greater risk of disabling neurological decline ²¹⁾ . Furthermore, in a retrospective study evaluating the effect of IV alteplase alone in individuals with mild stroke (NIHSS score ≤ 5), we reported that the presence of proximal LVO (ICA and MCA-M1) was an independent predictor of poor functional outcomes following IV alteplase administration ²²⁾ . Moreover, more proximal occlusion sites and longer thrombus length have been identified as independent risk factors for END following IV alteplase administration in individuals with minor ischemic stroke (NIHSS score ≤ 5) ¹⁵⁾ . In cases of acute cerebral infarction with LVO, bridging therapy, which involves MT in addition to IV alteplase, is commonly utilized ¹⁾ . However, the optimal approach for individuals with mild cerebral infarction and LVO remains a subject of debate. A retrospective observational study comparing IV alteplase alone with bridging therapy for mild cerebral infarction (NIHSS score ≤ 5) with LVO found that bridging therapy was particularly effective for MCA-M1 occlusion, whereas IV alteplase alone appeared more beneficial for MCA-M2 occlusion when considering the benefit-risk profile ²³⁾ . A meta-analysis of observational studies evaluating MT versus medical therapy for acute stroke in the M2 segment of the middle cerebral artery (MCA-M2) demonstrated that MT significantly improved clinical outcomes and reduced mortality in individuals with moderate to severe stroke (NIHSS score ≥ 6). However, in individuals with mild stroke (NIHSS score ≤ 5), no clear benefit of MT over medical therapy was observed ²⁴⁾ . For individuals with mild cerebral infarction and LVO, IV alteplase alone has demonstrated favorable outcomes, and there is currently no conclusive evidence supporting the routine use of endovascular therapy in combination with IV alteplase ^{25 , 26)} . However, based on previous studies, we believe that among LVO cases, proximal LVO, which is less likely to achieve successful recanalization with IV alteplase alone, should not be classified as mild cerebral infarction. Instead, such cases should be treated with MT for aggressive reperfusion, even if the neurological symptoms at the time of IV alteplase administration appear mild.

Ⅲ．Cases in which Medical Therapy is Recommended over IV Alteplase: Branch Atheromatous Disease (BAD)–Related Mild Stroke

BAD is a condition in which a relatively large-diameter perforating artery becomes occluded due to a thrombus originating from an atherosclerotic plaque at its bifurcation from a parent artery ²⁷⁾ . According to the TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification system, BAD is categorized as a “stroke of undetermined cause” due to its infarct size (＞15 mm) and the absence of significant stenosis in the parent artery ²⁸⁾ . A critical concern with BAD-related stroke is that, despite initially mild neurological symptoms at stroke onset, there is a high incidence of END, leading to worsening neurological function over time ^{27 , 29)} . Given that BAD is a form of non-cardiogenic cerebral infarction primarily caused by intracranial atherosclerosis, intensive antithrombotic therapy, most commonly DAPT, is typically initiated early in the disease course to mitigate the risk of END ^{27 , 30 , 31)} . The role of IV alteplase in BAD remains controversial. While some reports suggest that IV alteplase may be beneficial, others indicate a high rate of symptom recurrence and END following thrombolytic therapy. Currently, no definitive consensus has been established regarding the efficacy of IV alteplase for BAD-related stroke ^{22 , 32 - 35)} . In cases of BAD, preventing END is of paramount importance, and hemodynamic mechanisms are considered a key factor contributing to END ^{27 , 29)} . The lenticulostriate artery (LSA) is one of the primary perforating vessels implicated in BAD. Perfusion computed tomography studies of lacunar stroke in the LSA region have demonstrated that peri-infarct cerebral blood flow is reduced, and mean transit time is prolonged compared to the contralateral control region within the first 24 hours after stroke onset. Consequently, maintaining collateral blood flow via microcirculation from adjacent LSAs is reportedly a crucial factor in preventing infarct expansion in the LSA territory ³⁶⁾ . In our study of individuals with BAD in the LSA region who received IV alteplase, we found that the 24-hour average blood pressure (BP) following IV alteplase administration was lower in the END group than in the non-END group. Furthermore, we identified that BP control, particularly within the first 6 hours after alteplase administration, significantly influenced the occurrence of END ³⁷⁾ . These findings reinforce the role of hemodynamic impairment in the pathogenesis of END in BAD. Although further studies directly comparing IV alteplase with conservative treatment in BAD are warranted, we believe that when BAD is suspected based on imaging findings at presentation, IV alteplase should generally be avoided due to its requirement for strict BP control. Instead, intensive antithrombotic therapy, primarily antiplatelet therapy with Dual Pathway Inhibition, should be initiated in the acute phase to mitigate the risk of END ( Fig.1 ) ³⁸⁾ .

Fig.1. Treatment strategy for Branch atheromatous disease (BAD) Using Dual Pathway Inhibition: Pathways for thrombus formation and targets for oral antithrombotic agents.

ADP, adenosine diphosphate; COX, cyclooxygenase; cAMP, cyclic adenosine monophosphate; GP, glycoprotein; PDE, phosphodiesterase; TXA2, thromboxaneA2; vWF, von Willebrand factor

Ⅳ. A Potential Alternative to Alteplase for Patients with Minor Stroke: Tenecteplase

Tenecteplase (TNK) has garnered increasing attention as a thrombolytic therapy for acute stroke. TNK exhibits a longer half-life and greater fibrin specificity compared to alteplase, the conventional thrombolytic agent. Additionally, TNK is highly resistant to plasminogen activator inhibitor-1, and a single intravenous dose is sufficient to achieve thrombolysis ^{39 , 40)} . A meta-analysis has demonstrated that TNK is associated with a high recanalization rate, superior early neurological improvement, and comparable efficacy and safety to alteplase ^{41 - 56)} ( Fig.2 ) . European and American guidelines have already approved TNK as an alternative to alteplase and recommend its use at a dose of 0.25 mg/kg, particularly for individuals with acute stroke due to LVO who are candidates for MT ^{1 , 57)} . In Japan, the T-FLAVOR (Tenecteplase versus Alteplase for Large Vessel Occlusion Recanalization) trial is currently being conducted to assess the potential role of TNK in the management of acute cerebral infarction ⁵⁸⁾ . Additionally, the Norwegian Tenecteplase Stroke Trial (NOR-TEST), a large-scale study involving 1,100 individuals, was conducted to evaluate the safety and efficacy of TNK compared to alteplase in the setting of acute stroke ⁵⁹⁾ . The results demonstrated that TNK and alteplase exhibit comparable safety and efficacy profiles. The majority of individuals enrolled in this study had mild stroke, with a median NIHSS score of 4 (IQR 2–8), indicating that the study primarily targeted individuals with mild stroke. In a prospective study (TEMPO-1; TNK-Tissue-Type Plasminogen Activator Evaluation for Minor Ischemic Stroke With Proven Occlusion) evaluating two doses of TNK in individuals with mild cerebral infarction and intracranial occlusion (NIHSS score ≤ 5), higher doses of TNK were associated with greater complete recanalization rates. Furthermore, complete recanalization correlated with excellent functional outcomes at 90 days ⁶⁰⁾ . However, in a RCT (TEMPO-2; Tenecteplase versus standard of care for minor ischemic stroke with proven occlusion) designed to assess the efficacy of TNK in individuals with mild cerebral infarction (NIHSS score ≤ 5) and intracranial occlusion or focal perfusion abnormality, no significant benefit of TNK over standard non-thrombolytic care was observed ⁶¹⁾ . Additionally, due to an increased risk of intracranial hemorrhage, the trial was prematurely terminated. Given these findings, the efficacy of TNK in individuals with mild cerebral infarction and LVO requires further investigation. On the other hand, a study assessing the efficacy of TNK in individuals with BAD found that TNK significantly reduced the incidence of END and increased the proportion of favorable outcomes. The study used propensity score matching to compare individuals in the TNK group with those in the control group ^{62 , 63)} . Despite relatively sample size in these studies and direct comparisons with alteplase not being conducted, the findings suggest that TNK may be an effective treatment for BAD-related mild stroke.

Fig.2. Comparison of Alteplase (rt-PA) and Tenecteplase (TNK) as thrombolytic therapy in acute ischemic stroke: A visual representation of key findings from a recent meta-analysis ^{41 - 56)} .

The figure illustrates early neurological improvement, recanalization rates, functional outcomes, all-cause mortality, and the risk of symptomatic intracranial hemorrhage following rt-PA or TNK treatment in acute ischemic stroke patients.

Conclusions and Prospects

This review outlines the efficacy and limitations of rt-PA therapy in individuals with mild cerebral infarction. Our treatment strategy for rt-PA therapy in mild stroke is summarized in Fig.3 . Based on previous study results, individuals with acute stroke who present with mild, non-disabling symptoms (NIHSS score ≤ 5) and no evidence of LVO are generally less likely to benefit from rt-PA therapy (alteplase). In such cases, the risks associated with thrombolysis may outweigh the potential benefits. Additionally, for BAD-related mild stroke, emerging evidence suggests that a more favorable functional prognosis may be achieved with intensive antithrombotic therapy initiated in the hyperacute phase, without the need for rt-PA therapy. Conversely, in cases of mild stroke where LVO is present, rt-PA therapy remains an essential component of acute reperfusion therapy. Furthermore, for proximal LVO cases, MT should be strongly considered, even in individuals with mild cerebral infarction, to ensure optimal recanalization and prevent secondary infarct progression. Rather than adopting a uniform approach to rt-PA therapy in mild stroke, it is crucial to develop an individualized treatment strategy that accounts for the specific stroke etiology, vascular status, and potential for neurological deterioration in each case. A patient-centered, evidence-based approach to thrombolysis and endovascular intervention will be the key to improving outcomes in this heterogeneous population.

Fig.3. Proposed Treatment strategy for recombinant tissue plasminogen activator (rt-PA) Therapy in mild cerebral infarction: Authors’ perspective.

The figure outlines the decision-making strategy for the use of rt-PA in mild cerebral infarction. It categorizes treatment options based on stroke severity (NIHSS ≤ 5), presence of LVO, and suspected branch atheromatous disease (BAD), guiding whether medical management, rt-PA alone, or bridging therapy (MT + rt-PA) is recommended.

※ NIHSS score ≤ 5

BAD, Branch atheromatous disease; MT, mechanical thrombectomy

Ethics Statement

As this is a review article, no ethical approval was required. This study did not involve human participants, patient data, or laboratory animals.

Grant Support

This research was conducted without financial support from any public, commercial, or non-profit funding agency.

Conflicts of Interest

The authors declare that they have no conflicts of interest related to this research.