Stroke remains a leading cause of death and disability worldwide. Every year, 610,000 new people develop stroke in the United States of America and 140,000 die, making it the fifth leading cause of death [1]. Acute ischemic stroke accounts for 87% of all strokes and hence, restoring blood circulation to the ischemic area of the brain remains a very appealing treatment modality. There has been increasing use of thrombolytic agents for the treatment of acute ischemic stroke [2]. The NINDS study group conducted the first trial that established the use of intravenous recombinant tissue Plasminogen Activator (rt-PA) (Alteplase) as a thrombolytic agent for acute ischemic stroke [3]. Multiple studies have been conducted after this trial to investigate thrombolytic therapy for acute ischemic stroke. Most of these trials showed a trend towards an improvement in the functional outcome at the expense of increasing symptomatic intracranial hemorrhages. The results of various trials encouraged various stroke scientific bodies to approve rt-PA as a standard of care within the first three hours of symptoms onset.

The American Stroke Association expanded the recommendation to 4.5 hours of stroke onset after discussion of the risks and benefits with the patients [4]. Mechanical thrombectomy for acute ischemic stroke has commenced a new era of stroke management for a specific group of patients in the capable centers. A trial including patients who were last known to be well 6-24 hours earlier and had a mismatch between clinical deficit and infarct compared mechanical thrombectomy plus standard of care to the standard of care alone found better functional outcome in the mechanical thrombectomy group [5]. Based on this study, mechanical thrombectomy is recommended for patients with acute ischemic stroke due to a large artery occlusion who can be treated within 24 hours of symptoms onset. Patients are still eligible for rt-PA within the thrombolytic window, even if thrombectomy is being considered [6].

The previous systematic review investigated the safety and efficacy of thrombolytic agents when administered within 4.5 hours [7], which showed improvement in the functional outcome. Another review, which included studies investigating various thrombolytic agents, concluded that there is evidence of increased early mortality and rates of symptomatic intracranial hemorrhage with improved functional outcomes [8]. More research was thought to be needed to further assess the functional outcome and the mortality benefit of thrombolysis in acute stroke.

Given these recent developments in acute ischemic stroke care and questionable safety of delayed thrombolysis among studies, we conducted this systematic review to assess the functional outcome and mortality benefit in patients treated with fibrin specific thrombolytic agents for acute ischemic stroke within 6 hours of symptoms onset.

Our systematic review included a total of 9 studies and 6817 patients. All the trials included in the review satisfied high-quality scores using the JADAD scale. We used the random effect model as a more conservative approach of estimating the outcome of interest and adjusting for the variation between trials. The metanalysis provides good evidence that Alteplase given within 6 hours of acute ischemic stroke improves functional outcome at the expense of increased intracranial hemorrhage (fatal and symptomatic). Contrarily, the review does not support survival benefit at 6-months post thrombolytic therapy.

Our review demonstrated benefit beyond the current recommendations of 4.5 hours. The overall (OR for the functional outcome is 1.20 confidence interval [CI] 1.07–1.35) favoring intervention. The patients receiving thrombolytic therapy are likely to have less disability as measured by mRS or OHS. The I² score of 42% reflects a moderate statistical level of heterogeneity. Most of the studies have similar inclusion and exclusion criteria and hence have less clinical heterogeneity. Thrombolytic therapy within 6 hours post-stroke onset, resulted in a relative risk improvement RRI of 4%. Previous reviews demonstrated a diminishing benefit of Alteplase on the functional outcome with delayed administration. One review showed an RRI of 16% in the group of 3-4.5 hours and 6% for the group of delay longer than 4.5hours [7]. Although they found similar results and included most of the same trials, we simplified the question by searching at outcomes for patients within 6-hours of symptoms onset. In addition to Alteplase, we also searched for other fibrin specific thrombolytic therapy. Our search failed to find trials, which included other thrombolytic therapy that meets our criteria. Another review, which had a wider inclusion criterion, indicated a benefit with rtPA given within 6 hrs of ischemic stroke in the form of being alive and independent [8]. In contrast to our review, which replicates the usual clinical practice, they included some trials which used angiography to diagnose and verify the outcome of treatment in patients with CVA.

Fig. (4). Metanalysis of the effect of Alteplase on fatal and symptomatic ICH during for patient with CVA. C.I=Confidence Interval; ICH= intracerebral hemorrhage.

Fig. (5). Funnel plot for the included trials.

This metaanalysis demonstrated the known increased risk of fatal and symptomatic intracerebral hemorrhage (ICH) with OR of 5.61 and 5.36, respectively. For both analyses, the I² score was 0%, demonstrating a minimal statistical heterogeneity. One review reported the rate of ICH had not been affected by the delay in giving Alteplase and revealed the risk of ICH is highest in the group with Alteplase administered within 3 hours [7]. Despite the increased risk of ICH, we did not find a statistically significant increase in mortality for patients who received thrombolytic therapy, which is similar to the results reported by the previously mentioned review.

Our review has various limitations. The Funnel plot (Fig. 5) for mortality reflects a gap in the area of smaller studies, which might indicate small negative studies are likely not to get published. Despite being a limitation, we expect that if any studies were supporting such a benefit to be published. Our review is limited by the search only in English literature and predominantly on PubMed and Cochrane libraries. It may be missing some studies in other languages or on other libraries; however, we expected if they were any large RCT’s to have been referred to in our reference review. Two studies were found by a detailed reference review but failed to fulfill our criteria assessment [9, 10]. Another limitation is that the outcomes studied are short-termed (within six months only) with no long-term follow up. We expect all important outcomes for such treatment would have been reported within the study period.

We used the random effect model in our meta-analysis. It is a more conservative approach to consider variability between different trials. We did an exploratory analysis using a fixed-effect model, which did not significantly alter our inference results. A trial challenged the time limit for endovascular thrombectomy extending it beyond the 6 hours based on penumbral mismatch on MRI [5]. It revealed a benefit of functional independence at 90 days with no change in the symptomatic ICH rates. Another trial looked at extending the time limit for thrombolysis beyond the current 4.5 hours up to 9 hours based on identifying penumbral mismatch on MRIs to improve functional outcomes for late presenting stroke patients [11-19]. Results have not been published at the time of writing this manuscript.

Our review provides a good direction towards the possibility of extending the time window for administering Alteplase up to 6 hours with similar risks of ICH, perhaps with even better results utilizing MRI perfusion to better identify the right patients who would benefit from such therapy.

Dr. Abdullah Al Reesi contributed by writing the proposal, specifically the method section, performed the analysis and writing of the results and reviewed the manuscript.

Dr. Amal Al Mandhari and Dr. Marwan Al Raisi Reviewed the abstracts to be included in the review and summarized them. They contributed to the quality rating of the included studies and writing the manuscript.

Dr. Mahmood Al Jufaili, Fahad AL Abri and Huda AL Ruqaishi contributed to reviewing all the included trials, applying the inclusion and exclusion criteria and abstracting the data. The reviewed the manuscript.

All authors were involved in reviewing the manuscript and editing before the final submission. They gave permission to submit the manuscript for publication.

A poster presentation at the International Conference of Emergency Medicine 2019 (ICEM) in Seoul, Korea.