Intravenous Thrombolysis for Acute Ischemic Stroke with Extended Time Window

Introduction

Intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator (rt-PA) is a critical treatment option for acute ischemic stroke (AIS). Current international guidelines recommend that the optimal time for thrombolytic treatment is within 4.5 hours of stroke onset. However, only 5% to 25% of AIS patients receive rt-PA, primarily due to the restriction of this narrow treatment window. This limitation has spurred interest in exploring the potential benefits of IVT in patients with unclear stroke onset or those presenting beyond the 4.5-hour window.

Recent advancements in imaging technology, particularly magnetic resonance imaging (MRI), have provided new insights into the dynamic evolution of stroke. Diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) imaging have been used to identify acute ischemic lesions, suggesting that there may be a safe and effective therapeutic window for thrombolysis even beyond the traditional 4.5-hour limit. Additionally, the MRI perfusion-weighted imaging (PWI)/DWI mismatch pattern has been studied as a marker of ischemic penumbra, indicating that early reperfusion can lead to better recovery in patients with this mismatch.

Several trials have investigated the feasibility of extending the time window for IVT, with mixed results. This study aims to assess the effects of IVT in AIS patients with extended time windows or unclear symptom onset through a systematic review and meta-analysis of randomized controlled trials (RCTs).

Methods

Eligibility Criteria

The study included RCTs that compared IVT (IVT group) with placebo or usual care (control group [CG]) in AIS patients with unclear symptom onset or extended time windows (>4.5 hours). Eligible studies had to report outcomes such as favorable functional outcomes (modified Rankin Scale [mRS] scores 0–1), functional independence (mRS scores 0–2), symptomatic intracerebral hemorrhage (sICH), and death at 90 days. Studies that did not use alteplase for IVT, or were abstracts, reviews, or expert opinions, were excluded.

Search Strategy

The search was conducted in PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, and Google Scholar from inception up to April 2021. The search strategy included terms related to acute ischemic stroke, IV rt-PA, intravenous lysis, and thrombolysis. No language or region restrictions were applied. Reference lists of included trials were also reviewed.

Risk of Bias Assessment

The risk of bias in included trials was assessed using the Cochrane Risk of Bias tool, which evaluates sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessors, incomplete outcome data, selective reporting, and other biases. The overall risk of bias was categorized as low, high, or unclear.

Outcome Measures

The primary outcomes were favorable functional outcomes (mRS scores 0–1) and functional independence (mRS scores 0–2) at 90 days. Secondary outcomes included the proportion of patients with sICH and death at 90 days.

Data Extraction and Synthesis

Data were extracted independently by two reviewers, including baseline characteristics, intervention methods, time windows, and outcomes. Statistical analysis was performed using RevMan 5 software. The random-effects Mantel-Haenszel method was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for dichotomous data. Heterogeneity was assessed using the chi-square test and I² statistics. Subgroup analyses were conducted based on age (≤70 years or >70 years), National Institutes of Health Stroke Scale (NIHSS) scores (≤10 or >10), and time windows (4.5–9.0 hours or >9.0 hours). Funnel plots were used to assess publication bias.

Results

Search Results

The search identified four RCTs involving 848 patients. The trials were published between 2012 and 2019, with sample sizes ranging from 6 to 254 patients. All trials used alteplase 0.9 mg/kg for IVT. The mean time window in the IVT group ranged from 7.2 to 10.3 hours, and in the CG, it ranged from 7.3 to 10.4 hours. The average NIHSS scores in the IVT group ranged from 6 to 17, and in the CG, from 6 to 14.5.

Quality Assessment

The risk of bias in the included trials was generally low. Publication bias was assessed using funnel plots, which showed symmetry and low likelihood of bias.

Functional Outcomes

Three trials reported data on mRS scores 0–1 at 90 days, with 45.8% of patients in the IVT group achieving favorable outcomes compared to 36.7% in the CG (OR 1.48; 95% CI 1.12–1.96; P = 0.006). Four trials reported mRS scores 0–2 at 90 days, with 63.8% of patients in the IVT group achieving functional independence compared to 55.7% in the CG (OR 1.43; 95% CI 1.08–1.90; P = 0.02).

Symptomatic Intracerebral Hemorrhage

Four trials reported sICH, with 3.0% of patients in the IVT group experiencing sICH compared to 0.5% in the CG (OR 5.28; 95% CI 1.35–20.68; P = 0.02).

Mortality

Four trials reported mortality, with 7.0% of patients in the IVT group dying compared to 4.1% in the CG. However, the difference was not statistically significant (OR 1.80; 95% CI 0.97–3.34; P = 0.08).

Subgroup Analysis

Subgroup analyses showed that patients aged ≤70 years, with NIHSS scores ≤10, or with time windows >9 hours were more likely to achieve favorable functional outcomes with IVT. However, there were no significant differences in sICH or mortality across subgroups.

Discussion

This meta-analysis confirms that IVT can improve functional outcomes in AIS patients with extended time windows or unclear symptom onset, despite an increased risk of sICH. The findings are consistent with previous trials that have shown the benefits of IVT in patients with imaging evidence of salvageable brain tissue, such as PWI/DWI mismatch.

The higher incidence of sICH in the IVT group is a concern, but the overall benefits in terms of functional outcomes suggest that IVT may still be a viable option for carefully selected patients. The lack of a significant difference in mortality between the IVT and control groups further supports the potential benefits of extending the time window for IVT.

Limitations

This study has several limitations. First, the number of included trials and sample sizes were relatively small, which may limit the generalizability of the findings. Second, the trials used different methods for estimating mismatch and had varying clinical inclusion criteria, which could introduce heterogeneity. Third, subgroup analyses were limited by incomplete data and sample sizes, making it difficult to draw definitive conclusions about the effects of IVT in specific patient populations.

Conclusion

Despite these limitations, this meta-analysis suggests that IVT can improve functional outcomes in AIS patients with extended time windows or unclear symptom onset, although it may increase the risk of sICH. Future trials with larger sample sizes and more consistent methodologies are needed to confirm these findings and to further explore the potential benefits and risks of IVT in this patient population.

doi.org/10.1097/CM9.0000000000001781

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