Introduction

Stroke is one of the most significant causes of morbidity and mortality in the United States.[1] Based on data from the Centers for Disease Control and Prevention (CDC), an estimated 795,000 individuals experience acute ischemic strokes (AIS) annually, and at least 150,000 of these cases lead to fatalities.[2] The economic impact of AIS is significant, with the annual expenses for healthcare services, medications, and missed workdays totaling approximately $34 billion.[2] Unfortunately, adherence to expert consensus guidelines for treating AIS is not consistently observed, resulting in poorer functional outcomes. In response to this challenge, stroke centers have been established to standardize evidence-based protocols within the inpatient setting and enhance nationwide access to high-quality care.[3]

Stroke treatment has undergone significant and rapid advancements in the past 2 to 3 decades, with ongoing research continuing to influence and refine management practices. A critical breakthrough in stroke therapy occurred in 1996 when the Food and Drug Administration (FDA) approved thrombolytic therapy using alteplase—an intravenous (IV) recombinant tissue plasminogen activator (tPA). Although this treatment has demonstrated remarkable effectiveness for strokes resulting from small vessel occlusions, its efficacy for strokes caused by large vessel occlusions (LVO) has proven to be more limited.[4] 

Recent studies have examined the standard dose of alteplase, which involves administering 0.9 mg/kg alteplase IV, with a maximum total dose of 90 mg. This dose is given by administering 10% of the total dose as an initial IV bolus over 1 minute, followed by infusing the remainder over 60 minutes. These studies have compared this standard regimen with a rapid infusion of tenecteplase at 0.25 mg/kg. Multiple studies have shown that tenecteplase at both 0.1 and 0.25 mg/kg did not exhibit superiority over alteplase regarding neurological outcomes in patients with AIS within the 3- to 4.5-hour window. However, for patients with LVO, the results did not reach statistical significance.[4][5][6][7] 

The NEJM Campbell study revealed a statistically significant disparity in achieving greater than 50% reperfusion or unretrievable thrombus during a diagnostic angiogram. The study reported a rate of 22% with tenecteplase compared to 10% with the standard-dose alteplase. Furthermore, the tenecteplase group exhibited superior 90-day functional outcomes compared to the alteplase group. In various studies, meta-analyses have consistently demonstrated either non-inferiority or superior trending results for tenecteplase over alteplase.[8][9][10] 

In terms of safety, research findings have been somewhat varied, with some studies indicating a tendency toward fewer intracranial bleeding complications with low-dose tenecteplase (0.1 or 0.25 mg/kg) compared to high-dose tenecteplase (0.4 mg/kg) and standard-dose alteplase. A larger randomized controlled trial with a higher statistical power could provide valuable insights into the efficacy and safety profiles of tenecteplase compared to alteplase in LVO patients eligible for embolectomy.

Ideally, conducting studies at various time frames, such as 3 hours, 4.5 hours, 6 hours, and 6 to 24 hours before mechanical thrombectomy (MT), could offer valuable insights into whether tenecteplase exhibits superiority in cases of LVO. Further research will be necessary to determine whether tenecteplase can be more effective in treating AIS with LVO within 4.5 to 24 hours or in cases of early wake-up strokes.

The TIMELESS study is currently in progress and aims to evaluate the safety and efficacy of tenecteplase in patients eligible for imaging and those within the late-time window. The study reached its conclusion on November 30, 2021.[11]

LVO strokes are traditionally recognized as the most devastating in terms of morbidity and mortality. However, over the past 10 to 20 years, embolectomy or MT has significantly improved survival rates and functional outcomes for individuals with LVO strokes.[12][13][14][15] These groundbreaking therapies have revolutionized modern stroke care, establishing a new LVO treatment standard.

The implementation of MT brought about a shift in the stroke center certification classification, now mandating facilities to have the capability to perform this life-saving procedure.[16][17][18][19] The adage "time is the brain" emphasizes the critical importance of timely intervention. Earlier tPA administration is associated with improved functional outcomes, reduced intracranial bleeding risk, and lower hospital mortality rates. A mere 15-minute delay in tPA initiation is associated with a decline in the likelihood of achieving functional independence, surviving until discharge, accessing rehabilitation, and avoiding symptomatic intracranial bleeding. The odds of these outcomes decrease by 3% to 4% for every 15-minute delay interval.[20] For LVO strokes, early intervention is critical for patients undergoing MT. Each additional hour of delay in achieving MT reperfusion is associated with reduced functional independence, increased morbidity, and a diminished quality of life.[21]

According to the most recent guidelines released by the American Stroke Association (ASA) in 2018, eligible patients are advised to receive IV tPA as soon as possible, ideally within 3 hours of their last known normal state. In certain cases, selected patient groups may be considered for an extended time window of up to 4.5 hours. For eligible LVO patients, it is recommended to undergo MT as soon as possible, ideally within 6 to 16 hours from their last known normal. However, in certain cases, MT may still be a viable option within a broader time frame of up to 24 hours from the last known normal.[1] Given these recommendations, healthcare practitioners must be well-informed about stroke center accreditation levels and capabilities to initiate timely and appropriate treatment.

Function

Stroke centers were established following the publication of a consensus statement in the Journal of the American Medical Association in 2000. The Brain Attack Coalition (BAC), a collaboration of multiple professional stroke societies and regulatory agencies, played a pivotal role in shaping this groundbreaking consensus on stroke care. With the evolving landscape of medical treatment for stroke, additional consensus statements have been released. These statements have outlined the necessity for various types of stroke centers and have further defined their distinct capabilities and levels of treatment.

Stroke centers are established to improve the quality and coordination of acute stroke care. Certifying organizations possess the authority to reward designated facilities that adhere to evidence-based guidelines and can provide varying levels of care, ranging from fundamental to advanced stroke care. Several organizations, such as The Joint Commission (TJC), the Healthcare Facilities Accreditation Program (HFAP), Det Norske Veritas, Inc (DNV), and the Center for Improvement in Healthcare Quality (CHIQ), are involved in the certification process. These agencies assess various outcome measures, including healthcare team experience, patient volume, research initiatives, and survey frequency.

Stroke Center Classification

The most basic level of stroke center certification is the acute stroke-ready hospital (ASRH). These hospitals are equipped to perform rapid clinical stroke assessments, provide stabilization, and implement protocols for the safe administration of tPA. ASRHs are typically located in regions where primary stroke centers (PSCs) are not readily accessible. Upon the conclusion of the initial assessment and stabilization, patients are usually transferred to a more advanced stroke center for further evaluation and advanced diagnostic procedures. The establishment of ASRHs has significantly expanded the accessibility of initial stroke care in areas with limited resources, facilitating the seamless integration of patients into the broader stroke care system.[22] 

The ASRH's primary objective is to acknowledge hospitals that provide timely, evidence-based care to stroke patients before transferring them to a PSC or comprehensive stroke center (CSC).[22] ASRH certification is granted to eligible hospitals for a 2-year period following an on-site review. Organizations seeking this certification must meet specific requirements as outlined by TJC's Disease-Specific Care Certification program, which include the following:

• Maintaining a dedicated stroke-focused program.

• Staffing by qualified medical professionals specifically trained in stroke care.

• Collaborating with local Emergency Medical Services (EMS) to encourage training in field assessment tools and communication with the hospital before transporting stroke patients.

• Maintaining the capability for rapid diagnostic and laboratory testing around the clock, 24/7.

• Having the ability to administer IV clot-busting medications to eligible patients.

• Incorporating telemedicine technology into their services.

• Establishing transfer agreements or protocols with facilities that offer PSC or CSC.[22]

PSCs represent the next level of stroke center certification, which includes a dedicated interdisciplinary stroke team, access to advanced cerebrovascular imaging, and an inpatient stroke unit designed for the admission and care of patients with an AIS.[23][24] 

The PSC certification recognizes hospitals that adhere to specific standards designed to enhance stroke care and improve patient outcomes. These standards encompass a range of critical elements, including:

• Establishing a dedicated stroke-focused program.

• Ensuring staffing by qualified medical professionals specifically trained in stroke care.

• Providing individualized care tailored to meet the unique needs of stroke patients.

• Promoting patient involvement in their hospital care.

• Facilitating the coordination of post-discharge patient self-care.

• Ensuring a streamlined flow of patient information while protecting patient rights, security, and privacy.

• Collecting and maintaining the hospital's stroke-treatment performance data.

• Maintaining data on hospital team performance.

• Utilizing data to evaluate and continually enhance the quality of care.

The third level of stroke centers is referred to as thrombectomy-capable stroke centers (TSC). These institutions can provide 24/7 care for AIS patients and are equipped with an on-call neurovascular and neuro-interventional team and a dedicated neurological intensive care unit (ICU). The primary focus of TSCs is to provide MT for eligible patients, even if they may not meet all the criteria of CSCs. These TSCs receive certification from TJC, with the initial certifications commencing in 2018.

For a facility to be designated as a TSC, it must perform a specified minimum number of MT each year. TSCs are designed to ensure all the capabilities of PSCs while additionally possessing the capacity to deliver high-quality endovascular thrombectomy (EVT) and post-EVT care. In addition to their ability to perform MT, TSCs are required to establish transfer agreements with CSCs. These agreements facilitate the swift transfer of patients who encounter intracranial hemorrhages or present with cases that surpass the resources available at the TSC.

Although TSCs can provide MT, CSCs remain the preferred destination for patients with suspected LVO as determined by EMS triage. This preference is due to the limitations of clinical prediction rules for identifying LVOs in the field, which have limited sensitivity and specificity for identifying LVOS.[25] The development of TSCs exemplifies the agility and adaptability of stroke center frameworks.[26] These centers have neurointensive care units and maintain 24/7 on-site critical care coverage.

The CSC represents the highest level of stroke care, providing a comprehensive team of experts, including vascular neurologists, neurosurgeons, and vascular surgeons. The CSC Certification acknowledges hospitals that meet rigorous standards to deliver specialized care for the most complex stroke cases.

In addition to satisfying all the prerequisites for a PSC certification, CSCs must fulfill the following additional standards: 

• The availability of advanced imaging techniques, including magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), computed tomographic angiography (CTA), digital subtraction angiography (DSA), and transcranial Doppler (TCD) ultrasound.

• A team of personnel trained in vascular neurology, neurosurgery, and endovascular procedures.

• Round-the-clock accessibility to personnel, imaging, operating rooms, and endovascular facilities.

• The presence of ICU and neuroscience ICU facilities and the corresponding capabilities.

• A wealth of experience and expertise in treating patients with large ischemic strokes, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage.[27]

Issues of Concern

An ongoing debate and research in stroke care pertains to the most effective prehospital strategy for transferring stroke patients to the most appropriate stroke-certified center. The efficient and timely transportation and well-coordinated treatment protocols from lower- to higher-level stroke centers have significantly curtailed the administration times for tPA and MT procedures. A patient identified by EMS as having a stroke and located 15 minutes away from the nearest ASRH or PSC, and 30 minutes away from the closest TSC or CSC, may face a decision: which center should they choose for care?

Currently, 2 common routing strategies exist— the "drip-and-ship" and "mothership."

The Drip-and-Ship Strategy

Drip-and-ship is a prehospital transport strategy that entails the initial transportation of a stroke patient to the nearest stroke center, which may be an ASRH or PSC. The principal objective of this approach is to promptly initiate IV tPA for eligible patients who meet the criteria for such intervention.

Upon reaching the nearest stroke center, the patient undergoes rapid assessment and diagnostic imaging to ascertain the suitability for tPA administration. If advanced imaging identifies an LVO amenable to MT, the patient is transferred to a more distant TSC or CSC for specialized intervention.

The advantage of the drip-and-ship strategy lies in the swift initiation of IV tPA, which is critical for improving outcomes in certain stroke patients. Initiating tPA promptly at the nearest stroke center mitigates the risk of delays in thrombolytic treatment, potentially resulting in improved outcomes for patients who are candidates for this therapy.

In their research, Sheth and colleagues examined data from a substantial cohort of 44,667 patients who experienced ischemic strokes and received intravenous tPA treatment within 3 hours of symptom onset.[28] These data were sourced from the Get With The Guidelines-Stroke program, encompassing the period from April 2003 to October 2010 and involving 1440 hospitals. The study findings revealed that approximately 1 in 4 AIS patients who received tPA were treated through the drip-and-ship strategy. The outcomes for patients following this approach exhibited modest differences compared to those who were directly admitted to a stroke center and received tPA.[29]

The Mothership or Bypass Strategy

Mothership is a prehospital transport strategy that bypasses closer ASRHs or PSCs and directly transports the stroke patient to a TSC or CSC. The primary objective of this approach is to expedite the evaluation and potential MT for patients with AIS resulting from LVO.

The eligibility for MT is limited to patients with AIS caused by LVO. Hence, the "mothership" strategy is considered more reasonable if EMS can accurately recognize LVO cases in the field before making a hospital destination decision. To assist in identifying potential LVOs, EMS personnel utilize various stroke scales designed for prehospital detection. These screening tools include the Los Angeles Motor Scale (LAMS),[30] Cincinnati Prehospital Stroke Severity Scale (CSTAT),[31] Rapid Arterial Occlusion Evaluation (RACE),[32] and Field Assessment Stroke Triage for Emergency Destination (FAST-ED).[33] Selecting a particular screening tool often depends on regional stroke system preferences and the available resources.

In their meta-analyses and systematic review, Romoli et al examined data from patients with AIS who were eligible for reperfusion strategies. The mothership paradigm was associated with higher rates of functional independence at 3 months compared to the drip-and-ship strategy.[34]

The RACECAT randomized clinical trial addressed the critical issue of optimal prehospital triage for AIS patients. The trial's findings demonstrated a non-superiority or potential inferiority of the strategy that involved redirecting all LVO-suspected patients to the endovascular thrombectomy-capable stroke center (EVT-SC). This suggests that there was no distinct advantage in bypassing PSCs for EVT-SCs for all cases suspected of having LVO. Furthermore, although the findings were not statistically significant, the trend toward increased mortality among ICH patients within the EVT-SC group underscores that a particular subset of acute stroke patients might benefit from early triage at PSCs. For example, this could facilitate quicker blood pressure control and the rapid reversal of coagulopathic conditions.[35]

Strategy Algorithm 

The 2018 American Heart Association (AHA) and ASA guidelines state, "It remains unknown whether it would be beneficial for EMS to bypass a closer IV tPA-capable hospital for a thrombectomy-capable hospital." [1]

To address this uncertainty, the AHA and ASA have put forward an EMS triage algorithm to aid in decision-making. According to this algorithm, patients with suspected LVO and a last known normal time within 6 hours should be transported directly to the nearest TSC or CSC, as long as this bypass does not extend the transport time by more than 15 minutes and does not preclude the administration of IV tPA.

Future recommendations regarding prehospital triage will likely be influenced by ongoing research and studies investigating patient outcomes, the efficiency of field assessment tools for LVO identification, and the evaluation of regional healthcare resources.[1]

Additional concerns in stroke care encompass the need for comprehensive training of emergency department (ED) and hospital-based healthcare providers to keep up with the rapidly evolving stroke recommendations. Traditionally, providers may have primarily focused on evaluating an AIS patient for IV tPA eligibility. However, current guidelines underscore the significance of acquiring advanced multimodal neurovascular imaging to detect potential LVO and swiftly transferring suitably triaged patients to a TSC- or CSC-certified stroke center for potential MT.

Clinical Significance

Stroke remains a leading cause of morbidity, mortality, and healthcare expense in the United States. The burden of stroke is on the rise despite remarkable advancements in evidence-based acute care treatments and significant modifications in acute care stroke systems, procedures, and quality standards. 

Therapeutic approaches have been rapidly advancing in recent years, even for the most severe strokes. A comprehensive understanding of the specific stroke guidelines and the corresponding stroke center certifications is crucial in ensuring appropriate patient care and destination protocols. Timely recognition of stroke symptoms is paramount, as any delays in treatment can result in less favorable outcomes and could disqualify patients from vital medications or interventions capable of influencing the progression of their condition.[15]

Other Issues

The lack of standardization in stroke center certification is a valid concern that warrants attention.[23] Stroke centers can attain certification through various independent organizations such as TJC, DNV, and HFAP. Government agencies may also grant stroke center designations in certain regions, while some institutions opt for self-certification. The BAC strongly advocates for independent certification, a more accurate, rigorous, and comprehensive process for assessing stroke centers.[23]

A study investigating the quality of care and outcomes in PSCs participating in the "Get With The Guidelines" stroke data comparison identified statistically significant variations between certification organizations. Specifically, the study observed that the rate of IV tPA use was higher in PSCs certified by TJC and DNV, whereas it was lower in HFAP- and state-certified hospitals. Furthermore, compared to others, door-to-needle times were extended in hospitals certified by HFAP. In addition, state-certified PSCs had a higher in-hospital mortality rate.[36]

To address this issue, it may be essential for certification organizations and regulatory bodies to collaborate and establish unified guidelines and quality metrics for stroke care certification. By adopting standardized performance measures, stroke centers can be held to consistent and evidence-based benchmarks, thereby improving stroke care and ultimately resulting in improved patient outcomes.

Enhancing Healthcare Team Outcomes

Optimal stroke care relies on seamless coordination and effective communication among healthcare practitioners at all levels of the healthcare system. This collaborative approach commences with the initial contact of EMS with the patient and persists throughout the evaluation and treatment process. This involves a multidisciplinary stroke team encompassing clinicians, pharmacists, and nurses when the patient arrives at the hospital. The radiology department plays a crucial role in providing timely imaging. In some instances, acute surgical or endovascular interventions may be necessary, followed by inpatient and outpatient rehabilitation to support the patient's recovery. 

Efficient teamwork is fundamental for effective stroke therapy, as time-sensitive interventions are essential in stroke management. The entire stroke network, including EMS, hospital staff, and rehabilitation teams, must operate seamlessly to provide rapid identification and implementation of appropriate care. Early recognition of stroke symptoms and prompt communication among all components of the stroke care system are critical factors in improving patient outcomes.