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. [1][2][3][4]. 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. [5][6][7] 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 [8][9][10][11].  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. [12][13][14][15] 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. [16] 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.[17]

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.[18] 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.

Stroke centers were born from a consensus statement in the Journal of the American Medical Association in 2000. The Brain Attack Coalition (BAC) was a coalition of professional stroke societies and regulatory agencies that helped craft this important landmark consensus in stroke care. As treatment has evolved, further consensus statements have been published describing both the need for and capabilities of different levels of stroke centers and their corresponding levels of treatment. The objective of these centers is to improve the quality and organization of acute stroke care., Certifying organizations have the authority to reward designated facilities for following the evidence-based guidelines and having the ability to have basic and advanced levels of care. Some of these organizations include The Joint Commission (TJC), the Healthcare Facilities Accreditation Program (HFAP), and DNV GL Healthcare. Each agency has different outcome measures including healthcare team experience, patient volume, research, and survey frequency.

Stroke Center Classification

The most basic stroke center certification level is the acute stroke-ready hospital (ASRH). These hospitals perform appropriate clinical rapid stroke assessment, stabilization, and protocols for safe administration of tPA. They tend to be in areas without nearby primary stroke centers. After administration and stabilization, they are transferred to a higher-level stroke center for admission and advanced workup, as needed. ASRHs increase the availability of initial stroke care in areas with fewer resources and allow patients to be rapidly integrated into the greater stroke system.[19] Primary stroke centers (PSC) are the next level after ASRH, which includes a dedicated interdisciplinary stroke team, availability of advanced cerebrovascular imaging, and an inpatient stroke unit, to admit and care for patients with an AIS. [20][21] 

The third level of centers is called thrombectomy capable stroke centers (TSC), which have facilities that have an on-call neurovascular and neuro-interventional team that is able to provide 24/7 care to AIS and can monitor for complications of MT in a dedicated neurological ICU. First certified by TJC in 2018, these facilities are PSCs that are able to perform mechanical thrombectomy without all the requirements to be a comprehensive center. These centers have to perform a minimum of mechanical thrombectomies per year. The development of TSCs is an example of rapid adaptation within a larger and more defined stroke center framework.

The comprehensive stroke center (CSC) is the highest level of stroke care with a comprehensive team of vascular neurologists, neurosurgeons, vascular surgeons who perform cutting edge acute chemical treatments with tPA for AIS with stringent time-saving protocols related to administration and door-needle times for MT, advanced imaging (e.g. CT perfusion, magnetic resonance imaging with diffusion, magnetic resonance angiography, etc), and other more complex measures making it an all-in-one shop for acute stroke patients. Collaboration between many departments and access to the most advanced instrumentation is key to achieve this level. [22] As stroke therapy continues to advance, the stroke system will continue to evolve.

An area of active debate and research lies in the optimal prehospital strategy to transport stroke patients to the most appropriate stroke certified center. Timely transport and strategic coordinated treatment from lower to higher levels of definitive stroke centers can decrease tPA and mechanical thrombectomy times. A patient determined to have a stroke by Emergency Medical Services (EMS) is 15 minutes from the closest ASRH or PSC, and 30 minutes from TSC/CSC faces a dilemma, where should they go to first to obtain care? Should the patient go to a lower stroke center to receive rapid tPA ASRH/PSC for timely IV tPA or should the patient bypass the ASRH/PSC to the more distant TSC/CSC for possible mechanical thrombectomy? Currently, 2 basic routing strategies exist. They are known as "drip 'n ship" and "mothership."

The Drip 'n Ship Strategy

"Drip 'n ship" refers to the strategy of transporting the patient to the nearest stroke center to initiate IV tPA before transfer to a TSC/CSC for mechanical thrombectomy if advanced imaging reveals LVO amenable to intervention. This strategy minimizes delay to IV tPA administration at the risk of delaying time to possible mechanical thrombectomy.

The mothership or bypass Strategy

“Mothership” refers to the strategy of bypassing closer ASRHs/PSC stroke centers to go directly to a TSC or CSC for possible mechanical thrombectomy. This strategy minimizes delay to mechanical thrombectomy at the expense of delaying IV tPA. Only patients suffering AIS due to LVO would be eligible for mechanical thrombectomy and thus the bypass strategy is more reasonable if EMS can recognize LVO in the field before the hospital destination decision accurately. Numerous stroke scales are currently employed for EMS detection of possible LVO including the Los Angeles Motor Scale (LAMS),[23] Cincinnati Prehospital Stroke Severity Scale (CSTAT),[24] Rapid Arterial Occlusion Evaluation (RACE),[25] and Field Assessment Stroke Triage for Emergency Destination (FAST-ED).[26] The selection of a particular screening tool is generally based on regional stroke system preferences.

Strategy Algorithm 

The 2018 AHA/ASA guidelines state, "It remains unknown whether it would be beneficial for emergency medical services to bypass a closer IV tPA-capable hospital for a thrombectomy-capable hospital." The AHA/ASA has proposed an EMS triage algorithm that recommends patients with suspected LVO and last known normal within 6 hours be transported directly to the nearest TSC/CSC as long as the bypass does not add more than 15 minutes to transport and does not preclude the use of IV tPA. Research investigating patient outcomes and assessment tools along with consideration of regional resources will likely guide future recommendations.

Other issues of concern include the training of emergency department and hospital-based healthcare providers to appreciate and understand the rapidly evolving stroke recommendations. Providers previously may have only evaluated an AIS patient for IV tPA eligibility. However, providers now must obtain advanced multimodal neurovascular imaging to identify possible LVO and transfer the appropriately triaged patient to a TSC/CSC certified stroke center for mechanical thrombectomy.

Stroke remains a leading cause of morbidity, mortality, and healthcare expense in the United States. However, stroke care is now in a stage of rapid therapeutic advancement for even the most devastating strokes. It is critical for providers to understand current stroke guidelines and corresponding stroke center certifications for appropriate patient care and destination protocols. Timely recognition is also critical as treatment delays lead to poorer outcomes, and may even take patients out of treatment windows for an outcome changing medication or intervention.

The lack of stroke center certification standardization is a potential area of future concern. As previously discussed, stroke centers are currently certified through independent organizations (e.g.-TJC, DNV GL, HFAP). There are government agencies that, in some jurisdictions, may give stroke center designation and some institutions even elect self-certification. The BAC strongly endorses independent certification as that has been demonstrated to be more accurate, rigorous, and comprehensive a process.

One study examining the quality of care and outcomes in PSCs taking part in "Get With The Guidelines"-Stroke data comparison found statistically significant differences between certification organizations. The rate of IV tPA use was found to be higher in TJC and DNV GL and lower in HFAP and state-certified hospitals. Door-to-needle times were longer in HFAP hospitals, and state-certified PSCs had higher in-hospital mortality.[27] If this trend continues, changes in certification procedures may be necessary to ensure all designated stroke centers meet similar performance measures.