Stroke is a leading cause of morbidity and mortality in the United States. The Center for Disease Control and Prevention (CDC) reports that over 795,000 patients suffer from an acute ischemic stroke (AIS) every year with at least 150,000 fatal cases. The annual cost of health care services, medicines, and missed days of work approximated $34 billion. However, AIS may at times not be treated in accordance with expert consensus guidelines, leading to worse functional outcomes. Stroke centers aim to standardize evidence-based guidelines in the inpatient setting and increase access to quality of care nationally.
Stroke treatment has been an area of rapid development and progress over the past 2 to 3 decades, and recent studies continue to shape our management practices. Thrombolytic therapy with alteplase, an intravenous recombinant tissue plasminogen activator (tPA), was first approved in 1996 by the Food and Drug Administration (FDA). This treatment has been especially effective in treating strokes due to small vessel occlusions, but much less effective in treating strokes due to large vessel occlusions (LVO). Newer studies have compared standard dose of alteplase (0.9 mg/kg IV, 90 mg maximum as total dose; administer 10% of the total dose as an initial IV bolus over 1 minute and the remainder infused over 60 minutes) compared to a rapid infusion of tenecteplase 0.25 mg/kg. In several studies, it was shown that tenecteplase at 0.1 mg/kg and 0.25 mg/kg was non-superior (in neurological outcomes) to alteplase in a patient with acute ischemic stroke between 3-4.5 hours, however; there was a non-statistically significant trend in better neurological outcomes (e.g. 90-day modified ranking scale) in the tenecteplase compared to alteplase group in patients with large vessel occlusion. . Of note in the NEJM Campbell study, there was a statistically significant difference in => 50% reperfusion or unretrievable thrombus at the time of a diagnostic angiogram of 22% compared to 10% in those who had a standard dose of alteplase. Additionally, the tenecteplase group showed a 90-day superior functional outcome compared to the alteplase group. Meta-analysis has been performed with non-inferior or superiority trending results from the tenecteplase compared to the alteplase group.  In terms of safety profile, there are mixed study results with trends toward less intracranial bleeding complications with low dose (0.1 or 0.25 mg/kg) compared to high dose (0.4 mg/kg) tenecteplase and standard-dose alteplase. It is plausible that a larger RT double-blinded study that compares tenecteplase/alteplase with a higher power that focuses on LVO patients candidates for embolectomy versus non-candidates could yield interesting results in efficacy and safety profiles. Ideally, different time frames (3 hours, 4.5 hours, 6 hours, 6-24 hour timeframe) prior to mechanical thrombectomy could help determine whether tenecteplase could be superior in LVO. In summary, more research will be needed to determine whether tenecteplase could play a more instrumental role in large vessel occlusion AIS in the 4.5-24 hour window or in early wake-up strokes. Currently, the TIMELESS study (NCT03785678) is ongoing to determine the safety and efficacy profile of tenecteplase in imaging-eligible and late-window patients that are set to end November 30, 2021.
LVO strokes are traditionally the most devastating in terms of morbidity and mortality. In the last 10-20 years, the advent of embolectomy or mechanical thrombectomy (MT) has yielded significant survival and functional benefit for LVO strokes . These exciting new therapies have revolutionized modern stroke care for LVO, becoming a new standard of care. With the implementation of MT, there was a shift in the stroke center certification classification that included the capability of facilities to perform this life-saving procedure.  The more time brain tissue remains ischemic, the worse the patient’s neurological outcome. This concept is known as “time is brain.” Earlier tPA administration is associated with improved functional outcomes, decreased risk of intracranial bleed, and decreased hospital mortality. Initiating tPA is associated with worse odds of functional independence, death before discharge, rehabilitation, and symptomatic intracranial bleed in patients with delays of 15 minutes each hour. The worsening odds ranges between 3-4% every quarter of an hour.  For LVO, the importance of early intervention is critical in patients undergoing mechanical thrombectomy. Every one hour delay in MT reperfusion is associated with decreased functional independence and increased morbidity with poor quality of life.
The newest 2018 guidelines from American Stroke Association (ASA) recommend IV tPA be administered to eligible patients as early as possible and within 3 hours of last known normal with an extended window of 4.5 hours for a selective group of patients. Mechanical thrombectomy is also recommended as early as possible to eligible patients with LVO within 6 to16 hours of last known normal. Mechanical thrombectomy is considered reasonable in select patients within 6 to 24 hours of last known normal. Given these recommendations, it is critical for healthcare providers to have an understanding of stroke center certification levels and capabilities so that timely and appropriate treatment is initiated.