Safety and efficacy of intravenous thrombolysis: a systematic review and meta-analysis of 93,057 minor stroke patients

Acute ischemic stroke (AIS) is a severe cerebrovascular and neurological disease that can cause serious disability, morbidity, and mortality globally [1]. It is categorized into minor or mild with National Institutes of Health Stroke Scale (NIHSS) of ≤ 5, moderate from 6 to 15, and severe more than 15 [2]. The NIHSS is a 15-item assessment tool utilized to evaluate stroke severity. Initially created in 1989, it is now a commonly utilized outcome metric in stroke research. The current National Stroke Foundation guidelines endorse the NIHSS as a reliable instrument for evaluating stroke severity in emergency departments [3]. In literature, the NIHSS score and mRs are commonly employed to assess stroke severity and patient selection in studies, with varying cutoff NIHSS scores utilized by different research groups. Our research indicated that a cutoff NIHSS score of 5 or lower is the most commonly utilized in research projects [4]. The definition of minor ischemic stroke (MIS) is controversial, however the most accepted definition is a stroke with NIHSS ≤ 5 [5]. Nonetheless, a threshold NIHSS of 3 points or lower has been deemed appropriate for defining mild stroke in many studies [6], as patients within this cohort had improved outcomes after 90 days. Other studies characterize a mild stroke as an mRs score of < 2, acknowledging that the mRs provides insights into mortality risk and impairment, hence more effectively identifying patient needs post-hospital release [7]. Various research has presented several definitions for mild stroke; however, no consensus has been reached. MIS is common and is usually undervalued much by doctors or patients due to its mild symptoms. However, if the disease is not controlled at an early stage, it could rapidly deteriorate, increasing fatality and disability rates significantly [8]. Upon admission, approximately 50% of stroke patients experience a mild stroke [9, 10]. Additionally, roughly 30% of these patients have a handicapped outcome after 90 days and are unable to walk around on their own after discharge [11, 12].

Intravenous thrombolysis (IVT) is a treatment option for MIS. Alteplase, recombinant human tissue-type plasminogen activator (r-tPA), and tenecteplase, modified tPA with longer half-life, are fibrinolytic drugs used in IVT. IVT provides quick initiation of therapy, low costs, and requires no special equipment for treatment. Hence, aids in controlling AIS at an early stage. According to a study, alteplase treatment significantly improved AIS cases [13].

Four out of ten patients who got IVT therapy in national US practice had modest impairments, according to a previous study [11], which indicated that more than half of AIS hospitalizations had these conditions. Ninety days after a minor stroke, more than one-third of patients who did not receive alteplase treatment experienced functional impairment, despite only experiencing modest neurological symptoms at first [6, 14, 15]. As a result, alteplase was suggested as a treatment for AIS individuals who had minor disabilities in the 2019 guidelines [16]. In order to lessen the possibility of post-stroke impairment, alteplase treatment for mild strokes has grown recently [17, 18].

Previous studies have demonstrated that IVT is associated with short-term outcomes, such as home release, independent ambulation, or discharge with a good functional outcome measured by modified Rankin score (mRs) [11, 19, 20]. The mRs has served as the gold standard for assessing stroke outcomes in clinical studies for many years. This ordinal scale, which assesses patient impairment from 0 (no symptoms) to 6 (death), effectively encompasses the entire range of functional states while maintaining intuitive simplicity [21]. In the examination of somewhat higher baseline NIHSS, several observational studies indicated that IVT was related with good 90-day outcomes [10, 12, 22]. But in the Potential of rt-PA for Ischemic Strokes with Mild Symptoms (PRISMS) trial, alteplase was found to be equally safe and effective as aspirin for a favorable functional result after 90 days in non-disabling MIS (NIHSS ≤ 5). Rather, the probability of symptomatic intracerebral hemorrhage (sICH) was increased threefold by alteplase [13]. However, this trial ended prematurely and yielded little substantial evidence. Therefore, the subject of whether or not to use IVT to treat patients who have had mild or minor strokes has been debated in the modern era. Consequently, our goal was to determine whether IVT is safe and effective for treating minor stroke patients (NIHSS ≤ 5).

We conducted this study according to the principles of systematic reviews and meta-analysis indicated by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [23] and the Cochrane Handbook for Systematic Reviews of Interventions [24].

This meta-analysis compares the functional outcomes of MIS patients who received IVT with those who did not and evaluates the safety of IVT for MIS by comparing mortality and ICH rates between the two groups. Our findings revealed a significant difference in functional outcomes between MIS patients treated with or without IVT. Patients who received IVT treatment were more likely to have favorable functional outcomes 90 days after MIS. They had higher OR for (mRs 0–1) at 90 days as well as for improvement in NIHSS score when compared with the control group. Additionally, IVT treatment led to a reduction in the NIHSS score for the patients who received it, suggesting an improvement in functional outcomes.

Conflicting evidence exists in the literature regarding the efficacy and safety of IVT in MIS patients. The PRISMS was the first RCT to assess the impact of alteplase treatment in MIS patients. The study found that alteplase did not improve the chances of achieving a favorable functional outcome after 90 days compared with aspirin and was associated with a higher incidence of ICH [13]. This data was in line with a recent meta-analysis comparing IVT and dual antiplatelet therapy [46]. This difference from our study is due to various factors including smaller sample size, different comparison groups such as aspirin in the PRISMS study [13] and dual antiplatelet in the meta-analysis [46] in addition to other factors in the PRISMS study [13] including selection bias and subjective assessment of nondisabling stroke which is based on the assessors and differs between clinicians. Similarly, data from a multicenter nationwide database in China indicated that no significant benefit was observed for alteplase treatment compared with dual antiplatelet therapy or aspirin in MIS patients with a NIHSS score ranging from 0–3 [47].

On the other hand, a separate RCT study known as MINOR suggested that individuals treated with alteplase had notably improved functional outcomes after 90 days compared with those treated with aspirin [48]. A retrospective analysis using data from a multicenter registry database in Korea that involved 1384 minor stroke patients, found that IVT was associated with achieving a favorable outcome at 3 months when compared with those who did not receive IVT treatment [22]. Another retrospective analysis of an inpatient database in the United States, which included 103,765 patients with minor strokes, found that IVT was associated with a higher probability of patients being discharged directly to their homes without requiring assistance [11]. Also, a retrospective study of an Austrian Stroke Unit Registry, which included 890 MIS patients, suggested a potential benefit of IVT in MIS patients [33]. Moreover, Tu et al. [49] in their meta-analysis showed that IVT improves functional outcomes in minor stroke and doesn’t affect mortality when compared with routine medical management. Therefore, the treatment of MIS remains controversial in clinical practice.

Regarding the safety of IVT in MIS, our study showed that there were no statistically significant differences in mortality and ICH rates between the two groups, indicating that IVT is a relatively safe treatment option for MIS patients. These findings are in conformity with the observational studies [11, 22, 33] the MINOR RCT [48] and a previous meta-analysis including seven studies with 1591 patients [50]. There was a fear of the safety and long-term survival of the patients receiving IVT in MIS, however, the current pooled analysis showed that mortality measured at different time points was comparable between IVT and control in addition to comparable risk of the main adverse event of concerns which is ICH. This aligns with previous research which showed that on average, over a 10-year period, a patient receiving thrombolysis survives approximately one year longer than a comparable patient who did not receive thrombolysis, after adjusting for age, sex, prior anticoagulant treatment, acute phase NIHSS score, and subsequent antiplatelet therapy [51]. These findings augment and elaborate on earlier data from the Danish Stroke Register [52] and the subanalysis of the IST-3 trial [53] by illustrating that the advantages of thrombolysis for survival remain significant even up to 10 years post-stroke, while enhanced functional outcomes are still evident at 5 years.

Several factors play a role in the variability among the studies such as: age, gender, territory of the infarct, medical history and chronic medical conditions like hypertension, hyperlipidemia and diabetes. Additionally, the baseline NIHSS score was significantly higher for the IVT group compared with controls in several studies [10, 34, 36, 38]. These factors can immensely affect the functional outcomes in MIS patients. Kim et al. showed that patients with diabetes and deep middle cerebral artery (MCA) territory infarction had a poor prognosis after IVT [54] Moreover, impairment of the motor items in NIHSS was associated with poor outcome in MIS patients [55]. It’s also established that deep white matter or basal ganglia infarction have bad outcomes even after IVT or endovascular therapy (EVT) [56‐58]. treatment-related factors, such as differences in the onset-to-IVT time and dosage, may also affect outcomes. Not all the included studies specified the IVT dosage used. Some studies used a dosage of 0.9 mg/kg with a maximum dose of 90 mg, where 10% of the dose is given as an initial bolus and the remaining over one-hour intravenous infusion [35, 36]. Whereas Li et al. [8] used a dosage of 0.6 mg/kg with a maximum dose of 50 mg. The NOR-TEST research conducted in 2017 demonstrated that tenecteplase at a dosage of 0.4 mg/kg is as safe and efficacious as alteplase [59]. Due to the prevalence of mimics or mild strokes among the majority of patients in this study, identifying a significant difference proved challenging. NOR-TEST 2 was conducted to encompass patients with mild-to-severe ischemic stroke [60], revealing that 0.4 mg/kg tenecteplase was associated with elevated rates of sICH, mortality, and disability relative to 0.9 mg/kg alteplase, indicating that 0.4 mg/kg tenecteplase resulted in poorer functional outcomes compared with alteplase. This study determined that tenecteplase at 0.4 mg/kg is less effective than alteplase in treating moderate and severe ischemic strokes. Thus possibly, 0.25 mg/kg tenecteplase might be an alternative dosage among patients with ischemic stroke. The EXTEND-IA TNK trial conducted a direct comparison of 0.4 mg/kg and 0.25 mg/kg dosages of tenecteplase to ascertain the best dosage for individuals experiencing ischemic stroke [61]. They discovered no advantages to 0.4 mg/kg tenecteplase compared with 0.25 mg/kg in ischemic stroke patients. A recent study with 1,600 participants [62] indicated that tenecteplase at a dosage of 0.25 mg/kg is comparable to alteplase at 0.9 mg/kg for functional results, quality of life, and safety for patients with acute ischemic stroke. A recent meta-analysis of nonrandomized data comparing tenecteplase with alteplase found that neither individual RCTs nor prior meta-analyses have raised any safety concerns related to cerebral hemorrhage and death associated with tenecteplase in comparison to alteplase [63].

Not all MIS present have the same severity and personal characteristics. Therefore, it’s important to determine the subset of MIS patients that will benefit the most from IVT treatment.

Regarding the timing of IVT use, the current guidelines and recommendations demonstrated that IVT with recombinant alteplase is advised for individuals who have an acute mild debilitating ischemic stroke lasting less than 4.5 h [64, 65]. CT perfusion and perfusion-diffusion magnetic resonance imaging (MRI) can identify potentially viable brain tissue beyond 4.5 h post-stroke, and reperfusion through thrombolysis has demonstrated improved functional outcomes in patients with salvageable brain tissue beyond this timeframe [66‐68]. Regarding the type of stroke, IVT is recommended as a mainstay of treatment in ischemic stroke and should be avoid in hemorrhagic stroke due to the increased risk of bleeding which causes ICH [69].

It seems that MIS patients with infarcts in locations that don’t involve deep MCA territory, deep white matter or basal ganglia have better functional outcomes [54, 56‐58]. Also, IVT was not associated with better functional outcomes in MIS patients with a NIHSS baseline score of 0–1 [10]. This is due to the increased risk of early neurological deterioration (END), which can reach up to 14% in patients receiving IVT [70]. The etiology behind END in these cases include reperfusion injury, effects of hyperglycemia, or re-embolization [71].

In patients with MIS, it seems that EVT does not significantly improve functional outcomes when compared with standard medical treatment [72]. However, it's crucial to consider that the effectiveness of EVT as well as IVT can be influenced by various factors, including the severity of the stroke, the location of the clot, the timing of treatment, and individual patient characteristics. EVT is typically reserved for acute ischemic strokes caused by significant vessel occlusions, and its benefits may vary depending on the clinical context.

Our meta-analysis was limited by the number of studies in the literature as well as the variability of data. Moreover, describing what constitutes a "minor" or “mild” stroke in terms of the type and severity of neurological deficits can be challenging due to the lack of a universally agreed-upon definition. To address this issue, some studies use the NIHSS score as a cut-off value to define a minor stroke. However, not all neurological deficits that arise from a minor stroke are effectively assessed using the NIHSS. The scale may not accurately capture strokes in the posterior circulation or the right hemisphere. On the NIHSS, a patient with severe language impairment can have the same score as patient with mild facial weakness, mild dysarthria, and a mild drift of an upper extremity (NIHSS score = 3). However, it is widely agreed among clinicians that a severe language impairment is more disabling for the patient. Therefore, there is a need to redefine what constitutes a minor stroke and how it is diagnosed in clinical practice. Also, the meta-analysis is limited by the predominance of observational studies that act as a major source of bias and no causal relationship, however, limited RCTs regarding this topic is frequently published. This limitation may decrease the evidence of the conclusion, but it reflects real world data of the use of IVT in MIS. Although, the meta-analysis showed homogenous findings in most of the outcomes, some outcomes were observed to have significant heterogeneity. However, this heterogeneity was caused by a single study as we clarified in the sensitivity analysis by leave-one-out methods and provided the reasons for some extreme results.

While some studies have not found any advantages of IVT in MIS patients, a significant body of literature strongly supports IVT as an effective and safe treatment for MIS. IVT has been shown to improve the mRs and NIHSS scores at the 90-day mark without an increased risk of ICH or mortality. IVT, according to the current analysis, is safe and effective in patients with minor or mild stroke with NIHSS ≤ 5 and this is supported by real world data and large sample size from various centers which can be applied generally. However, there is a need to refine MIS treatment protocols and conduct more RCTs to confirm these findings as RCTs are associated with higher evidence. The current gap in the current research is the most effective and safest dose of IVT drugs to be used in the treatment of MIS and the best timing for it. Also, the risk of END needs further investigation and providing an adequate definition of NIHSS needs to be adjusted across all centers.