Intravenous Thrombolysis in an Endovascular Treatment–Dominant Era: What Does the Future Hold?

Abstract

The definitive target of acute ischemic stroke is rapid and effective reperfusion. This is vastly conditional on rapid recognition of symptoms and efficient transport mechanisms that bring the patient to optimal health care facility. This review summarizes evidence from cardiology in this field and highlights the need of such measures to be incorporated in systems of care for stroke, and further information is needed to develop efficient systems of care at a regional and hospital level.

Nonstandard Abbreviations and Acronyms

AcT

Alteplase Compared to Tenecteplase in Patients With Acute Ischemic Stroke

ASPECTS

Alberta Stroke Program Early Computed Tomography Score

ASSENT

Assessment of the Safety and Efficacy of a New Thrombolytic Regimen

CSC

comprehensive stroke center

DAWN

DWI or CTP Assessment With Clinical Mismatch in the Triage of Wake‐Up and Late Presenting Strokes Undergoing Neurointervention With Trevo

DEFUSE‐3

third Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke

DEVT

Direct Endovascular Thrombectomy vs Combined IVT and Endovascular Thrombectomy for Patients With Acute Large Vessel Occlusion in the Anterior Circulation

DIRECT‐MT

Direct Intra‐arterial Thrombectomy in Order to Revascularize AIS Patients With Large‐Vessel Occlusion Efficiently in Chinese Tertiary Hospitals: A Multicenter Randomized Clinical Trial

DIRECT‐SAFE

A Randomized Controlled Trial of DIRECT Endovascular Clot Retrieval versus Standard Bridging Therapy

ECASS‐III

third European Cooperative Acute Stroke Study

EPITHET

Echoplanar Imaging Thrombolytic Evaluation Trial

ESOC

European Stroke Organisation Conference

EVT

endovascular treatment

GISSI‐1

Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto‐1

GUSTO‐1

Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries

IST‐3

third International Stroke Trial

IVT

intravenous thrombolysis

LVO

large vessel occlusion

MR CLEAN‐NO IV

Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands

NINDS

National Institute of Neurological Disorders and Stroke Recombinant Tissue Plasminogen Activator Stroke

PAMI

Primary Angioplasty for Myocardial Infarction

RACECAT

Transfer to the Closest Local Stroke Center vs Direct Transfer to Endovascular Stroke Center of Acute Stroke Patients With Suspected Large Vessel Occlusion in the Catalan Territory

SHRINE

Systemic Thrombolysis Randomization In Endovascular Stroke Therapy

SKIP

Randomized Study of EVT With Versus Without Intravenous Recombinant Tissue‐Type Plasminogen Activator in Acute Stroke With ICA and M1 Occlusion

STREAM

Strategic Reperfusion Early After Myocardial Infarction

SWIFT‐DIRECT

Solitaire With the Intention For Thrombectomy Plus Intravenous t‐PA Versus DIRECT Solitaire Stent‐retriever Thrombectomy in Acute Anterior Circulation Stroke

Clinical Perspective

• What Is New?

• This review recapitulates the advancement of reperfusion strategies as well as the organization of transport systems in the management of acute myocardial infarction.

• It also highlights the need of such measures to be incorporated in systems of care for stroke, and further information is needed to develop efficient systems of care at a regional and hospital level.

• What Are the Clinical Implications?

• These considerations may lead to the following recommendations:

• First, a regional stroke system needs to be organized to determine the best transport strategy on a case‐by‐case basis instead of routinely transporting patients to the nearest hospital. Stroke patients’ clinical presentation, potential treatment modality, logistics, and accessibility to the hospital should be considered.

• Second, if indicated for endovascular treatment, intravenous treatment may be delayed until the condition is made that the benefit of intravenous treatment is higher than endovascular treatment, such as in cases with distal embolization after opening the main occlusion or recanalization failure.

• Third, tenecteplase should be considered as the thrombolytic of choice in such settings given its advantages over alteplase.

• To test these hypotheses, a randomized clinical trial deeply rooted in regional stroke systems is warranted.

The ultimate goal of treatment in acute ischemic stroke is timely restoration of cerebral blood flow before accumulation of irreversible ischemic changes. To facilitate efficient transport of patients with stroke symptoms, current guidelines recommend using a validated and standardized instrument for rapid screening and building of a regional transfer system. ¹ , ² These guidelines also recommend that patients with suspected stroke should be transported rapidly to the closest health care facilities that can rapidly administer intravenous thrombolysis (IVT; fast thrombolysis approach). ³ IVT is fast, easy to administer, readily available, can be given at a primary stroke center, and does not require expert intervention. However, the efficacy of thrombolysis is limited because of its relatively lower rates of recanalization for patients with large vessel occlusion (LVO), with potential risks of systemic and intracranial hemorrhage. ⁴ , ⁵ , ⁶ In contrast, endovascular therapy achieves substantially higher rates of thrombus recanalization but requires patients to be transferred to a comprehensive stroke center (CSC), potentially resulting in delay of acute treatment. Moreover, endovascular treatment (EVT) is resource intensive, requires expert neurointerventionists and supporting teams, is operator‐dependent, and can result in procedural complications (eg, vasospasm, vessel perforation, and emboli in new territory). Currently, recommendations on target destination for patients who are likely to have an LVO (fast thrombectomy approach) are limited by lack of robust evidence. ⁷ Moreover, data from recent clinical trials on the extent to which thrombolysis is a meaningful addition to the EVT paradigm in patients with LVO are conflicting at best. In addition, it is unclear how a transport paradigm that prioritizes IVT first followed by EVT compares with the fast thrombectomy paradigm that prioritizes transport of patients with suspected LVO to a CSC for EVT, especially across different geographies and health systems. ⁸ , ⁹ , ¹⁰ Of relevance, however, is that this comparison between a fast thrombolysis versus fast thrombectomy strategy has been attempted in a different field of medicine, ie, in patients with acute myocardial infarction (AMI), at least a decade earlier from which we can draw many lessons. In this review, therefore, we focus on the present state of IVT in the current EVT‐dominant era of acute stroke, review reperfusion strategies for AMI and discuss how these insights may help us in designing studies that will better inform future systems of stroke care that offer both IVT and EVT in acute stroke.

Advances in the Reperfusion Strategies for Patients with STEMI

Similar to the pathophysiology of ischemic stroke, acute ST‐segment–elevation myocardial infarction (STEMI) is also caused by sudden occlusion of a coronary artery that perfuses the myocardium. Therefore, rapid reconstitution of myocardial blood supply through intravenous fibrinolysis or percutaneous coronary intervention (PCI) is the recommended strategy for treatment of this condition. This section will provide a brief historical overview of the development of reperfusion treatment for patients with STEMI and extract strategic lessons with potential to inform modern acute stroke management.

The historical development of reperfusion strategy for acute STEMI seems to share a common ground with the advances in treatment of acute ischemic stroke. The landmark GISSI‐1 (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto‐1) trial (1986) randomized 11 806 patients with AMI into streptokinase versus usual treatment and showed a survival benefit from streptokinase when administered within 24 hours after symptom onset. ¹¹ In a post hoc analysis of the GISSI‐1 trial, efficacy of fibrinolytic was reported to be a function of time, and the maximal benefit from the fibrinolysis was to be expected when initiated within 2 hours of symptom onset, thus leading to the development of the concept of “golden hour” in AMI treatment. ¹² Over time, more fibrin‐specific fibrinolytic drugs were developed, including tissue plasminogen activator (alteplase) and tenecteplase. These second‐generation fibrinolytic drugs secured their equivalent efficacy to streptokinase through the GUSTO‐1 (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) (tissue plasminogen activator) ¹³ and ASSENT (Assessment of the Safety and Efficacy of a New Thrombolytic Regimen) (tenecteplase) trials. ¹⁴ On the other hand, the benefit of PCI with angioplasty was evident with the pivotal PAMI (Primary Angioplasty for Myocardial Infarction) trial, which showed that immediate PCI within 12 hours from symptom onset reduced the combined occurrence of nonfatal reinfarction or death with a lower rate of intracerebral hemorrhage. ¹⁵

Keeping all of the above evidence in mind, a pharmacoinvasive approach for management of AMI was proposed. This entailed combination of fibrinolytic therapy followed by angiography ± PCI, either immediately if there is evidence of failed fibrinolysis or at a later time point in case of successful fibrinolysis. ¹⁶ The evidence showed that survival gain from the primary PCI over intravenous fibrinolysis is achievable when PCI is initiated within 120 minutes (Figure 1A). In the STREAM (Strategic Reperfusion Early After Myocardial Infarction) trial published in 2013, the feasibility of this pharmacoinvasive strategy was tested in clinical practice. ¹⁷ The trial showed that prehospital fibrinolysis with timely coronary angiography is an effective reperfusion strategy in patients who cannot undergo primary PCI within 1 hour of first medical contact. The most current cardiology guidelines adapt this pharmacoinvasive approach and recommend transferring patients with STEMI for the primary PCI if this can be achieved within 120 minutes after the first medical contact, or starting intravenous fibrinolysis immediately if such transfer cannot be achieved. ¹⁸ , ¹⁹

Figure 1.

Known relations of time‐to‐treatment to benefit of reperfusion therapies, including: (A) for ST‐segment–elevation myocardial infarction (STEMI), (B) thrombolysis in stroke, and (C) endovascular treatment (EVT) in stroke. cOR indicates common odds ratio; LVO, large vessel occlusion; mRS, modified Rankin Scale; and PCI percutaneous coronary intervention.

Lessons that can be Learned from Cardiology

From the cardiac literature review, we recognize historical similarities to how acute stroke is evolving as a field. Our current treatment strategy is to treat patients with acute ischemic stroke within 4.5 hours of symptom onset with IVT followed by evaluation for possible EVT and to treat all patients with LVO with salvageable brain up until 24 hours from last known well. The prehospital phase of acute stroke care is focused on identifying patients with: (1) acute ischemic stroke within 4.5 hours from symptom onset for IVT, and (2) patients with major disabling stroke and LVOs for transfer to a CSC for EVT. Most current systems of acute stroke care prioritize IVT administration, per available evidence and guidelines (Table 1). At the time of evaluation of a patient with suspected stroke at the scene, key factors in the decision to determine where to transport the patient include severity of symptoms, likelihood of the stroke being ischemic in nature, likelihood of the stroke being caused by an LVO, time from stroke onset to assessment, and time to transport to a primary stroke center versus a CSC along with the probability of reperfusion spontaneously versus with IVT or with EVT. Although statistical models are being designed to help with such decision‐making, they are not easily available and are often not specific enough for the individual patient. ⁹ , ²⁰ Similar challenges exist even when a patient presents to the CSC directly, especially during the daytime when the angiography suite is available to use and the interventional team is on standby.

Table 1.

Guideline Recommendations on Prehospital Stroke Care

	AHA/ASA guidelines 2019 (strength of recommendation) 3	ESOC 2019 guidelines (strength of recommendation) 2	Australian guidelines, 2021 (strength of recommendation) 46	Canadian Best Practice, 2022 (strength of recommendation) 42
Prehospital transfer	Patients with a positive stroke screen or who are strongly suspected to have a stroke should be transported rapidly to the closest healthcare facilities that are able to administer intravenous alteplase. (Strong, moderate quality)	As there is a lack of randomized evidence for superiority of one organizational model, the choice of model should depend on local and regional service organization and patient characteristics (Grade C – within group consensus, limited evidence)	Ambulance services should preferentially transfer patients with suspected stroke to a hospital capable of delivering reperfusion therapies as well as stroke unit care (strong)	Direct transport protocols must be in place to facilitate the transfer of patients with suspected acute stroke who are potentially eligible for thrombolytic and/or endovascular thrombectomy to the most appropriate acute care hospital capable of providing services for the diagnosis and treatment of acute stroke (Strong recommendation‐moderate quality of evidence)
IVT‐eligible transfer to PSC vs CSC	When several intravenous alteplase–capable hospital options exist within a defined geographic region, the benefit of bypassing the closest to bring the patient to one that offers a higher level of stroke care, including mechanical thrombectomy, is uncertain (weak, moderate quality)	For patients without an identified contraindication to IVT, if estimated transportation time to a CSC is considerably longer than transportation to the nearest PSC (≈>30−45 minutes), the drip‐and‐ship model should be considered (Grade C – within‐group consensus, limited evidence)	No recommendations	a. Patients who may be eligible for intravenous thrombolysis may be directed to the closest centre, which may be a primary/advanced stroke centre or comprehensive stroke centre. b. Patients who are likely candidates for EVT may be directed to (1) an EVT‐enabled comprehensive stroke centre OR (2) a primary centre to rapidly receive intravenous thrombolysis and then be considered for transport to an EVT‐enabled comprehensive stroke centre.
Suspected LVO transfer	Effective prehospital procedures to identify patients who are ineligible for IVT and have a strong probability of LVO stroke should be developed to facilitate rapid transport of patients potentially eligible for thrombectomy to the closest healthcare facilities that are able to perform mechanical thrombectomy (weak, expert opinion)	Conversely, if the difference in travel time between the nearest PSC and the nearest CSC is <30−45 minutes, or if contraindications to IVT are suspected in the field (ie, recent surgery, oral anticoagulation…), direct transportation to the CSC should be considered if LAO is deemed clinically plausible (Grade C – within group consensus, limited evidence)	No recommendation	For EVT‐eligible patients, processes and or algorithms should be put in place that will easily enable a discussion to arrange for the patient to be transferred to the EVT‐enabled comprehensive stroke centre in a timely manner. A three‐way conference call among the referring clinician (paramedic or emergency department physician at a primary/advanced stroke centre), the receiving physician at the EVT‐enabled centre, and the ambulance service involved in patient transport should support decision‐making regarding direct to EVT centre or closer centre for initial imaging and assessment.
Door‐in and door‐out time in drip‐and‐ship	No recommendation	The first picture‐to‐puncture time and the door‐in‐door‐out time in drip‐and‐ship patients should be as low as possible, ideally <90 minutes and <60 minutes, respectively (Grade C – within group consensus, limited evidence)	No recommendation

AHA indicates American Heart Association; ASA, American Stroke Association; CSC, comprehensive stroke center; ESOC, European Stroke Organisation Conference; IVT, intravenous thrombolysis; LVO, large vessel occlusion; PSC, primary stroke center; and RCT, randomized controlled trial.

Review of Current Evidence: Efficacy of IVT Versus EVT in Intravenous‐Eligible Stroke

The efficacy of IVT was established through the pivotal NINDS (National Institute of Neurological Disorders and Stroke Recombinant Tissue Plasminogen Activator Stroke) trial in 1995, ²¹ which was followed by expansion of thrombolysis time window via EPITHET (Echoplanar Imaging Thrombolytic Evaluation Trial), ECASS‐III (third European Cooperative Acute Stroke Study), and IST‐3 (third International Stroke Trial). ²² , ²³ , ²⁴ , ²⁵ It was only recently (2015) that endovascular therapy secured its role in acute stroke management ²⁶ despite the Honolulu shock in 2013. ²⁷ Despite being a relatively new technique, the acute stroke world has seen major leaps in EVT, the latest being the expansion of time window up to 16 or 24 hours from the time last known well via the DAWN (DWI or CTP Assessment With Clinical Mismatch in the Triage of Wake‐Up and Late Presenting Strokes Undergoing Neurointervention With Trevo) ²⁸ and DEFUSE‐3 (third Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke) ²⁹ trials. These trials have shown that select patients might benefit from recanalization treatment up to 16 or 24 hours from presumed onset. ²⁸ , ²⁹ Both of these therapies are time dependent and reduction of treatment benefit by time has been demonstrated from results of major clinical trials involving IVT as well as endovascular recanalization treatment ²⁵ , ³⁰ (Figure 1B, C).

A more approach‐based question on the utility of thrombolysis in the setting of LVO was tested in 5 IVT bridging trials (Table 2). The underlying hypothesis for all of these trials was that the direct EVT approach is either noninferior or superior to bridging with thrombolysis in patients who present with an LVO to a CSC (Table 2). First, DIRECT‐MT (Direct Intra‐arterial Thrombectomy in Order to Revascularize AIS Patients With Large‐Vessel Occlusion Efficiently in Chinese Tertiary Hospitals: A Multicenter Randomized Clinical Trial) ³¹ from central and western China tested for noninferiority and randomized patients with direct EVT versus both EVT and thrombolysis groups and found similar rates of successful recanalization and functional recovery in both groups. The overall rates of good outcome (modified Rankin scale 0–2 at 90 days) in this trial were low (36.4% in the EVT‐alone group and 36.7% in the combined arm) and one of the potential reasons could be that less than one‐third of these patients had good–moderate collaterals and the workflow times in the trial were longer as compared with previously published data. Rates of emboli in new territory were similar in both groups (10.7% in the direct group versus 9.4% in the combined arm). Second, SKIP (Randomized Study of EVT With Versus Without Intravenous Recombinant Tissue‐Type Plasminogen Activator in Acute Stroke With ICA and M1 Occlusion) ³² from Japan tested for noninferiority as well but used a lower dose of alteplase (0.6 mg/kg) and a restricted patient population up to 84 years with exclusion of patients with low ASPECTS (Alberta Stroke Program Early Computed Tomography Score) (< 6) and M2 occlusion. The trial could not prove noninferiority but had a high proportion of good outcomes (59.4% in the EVT‐alone group versus 57.3% in the combined group) with workflow times comparable with western populations. No data on collateral circulation were published and rates of clot migration were similar in both groups (25% in the direct group versus 27% in the combined arm). Third, the DEVT (Direct Endovascular Thrombectomy vs Combined IVT and Endovascular Thrombectomy for Patients With Acute Large Vessel Occlusion in the Anterior Circulation) trial ³³ from eastern China also assessed for noninferiority and did not have any restrictions on age, baseline National Institutes of Health Stroke Scale, and ASPECTS. The trial did not find a significant difference in rates of good outcome (54.3% in the direct arm versus 46.6% in the combined arm). Two‐thirds of patients had moderate–good collaterals at baseline, and rates of clot migration were not statistically different between the 2 groups (17.7% in the direct arm versus 23.9% in the combined arm). Fourth, the results of MR CLEAN‐NO IV (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) is the only trial that tested for superiority and had the most pragmatic trial design incorporating deferral of consent and no strict inclusion criteria. The rates of good clinical outcome were similar in both groups (51.1% in the direct arm versus 49.1% in the combined arm) and the trial failed to show superiority. ³⁴ The trial also had an option to give rescue alteplase in the direct arm; however, these were only a minority. ³⁴ A patient‐level pooled analysis of the SKIP and DEVT trials, the SHRINE (Systemic Thrombolysis Randomization In Endovascular Stroke Therapy) collaboration, was also presented at the International Stroke Conference meeting and had similar results as these individual trial results. Last, the results of the SWIFT‐DIRECT (Solitaire With the Intention For Thrombectomy Plus Intravenous t‐PA Versus DIRECT Solitaire Stent‐retriever Thrombectomy in Acute Anterior Circulation Stroke) and DIRECT‐SAFE (A Randomized Controlled Trial of DIRECT Endovascular Clot Retrieval versus Standard Bridging Therapy) trials also confirmed these findings and showed that direct EVT failed to show noninferiority as compared with the combined approach (good outcome modified Rankin scale 0 to 2: 65% in the combined arm versus 57% in the direct arm). ³⁵ , ³⁶ Yet another point to consider is that the trials that tested for noninferiority (all except MR CLEAN‐NO IV) have been criticized for their selection of wide noninferiority margins based on a fixed margins approach over minimal clinically important difference, and these margins may not be acceptable to many practicing stroke physicians. A combined meta‐analysis presented at the European Stroke Organisation Conference 2021 showed that proof of noninferiority was dependent on these lower boundaries, and combined results could prove noninferiority of direct approach over the combined approach when more relaxed noninferiority margins (eg, −15%, −10%, and −6.5%) were chosen. However, stricter noninferiority margins such as −5%, −3%, and −1.5% extrapolated on the basis of physician‐preferred minimal clinically important differences failed to prove this hypothesis. ³⁷ In addition, these trials include only patients who arrived at a CSC and thus, these results do not apply to patients for whom the interdependent bridging plus transport questions matter. Analysis of in‐hospital workflow times in these trials did not show a significant difference in the bridging versus direct thrombectomy groups. ³⁸ , ³⁹

Table 2.

Summary of Bridging Thrombolysis Trials

Name	Design	Noninferiority margin	Lytic agent	Size	Population	Results	Door‐to‐needle time (median)	Door‐to‐puncture time (median)
DIRECT‐MT 31	Noninferiority	OR, 0.8 (lower bound of the 95% CI); 2‐sided α=0.05, power=0.8	t‐PA (0.9 mg/kg)	640	China	Direct mechanical thrombectomy was noninferior	59 min	84 min for mechanical thrombectomy‐alone group, 85.5 min for combined group
SKIP 32	Noninferiority	OR, 0.74; 1‐sided α=0.025, power=0.8	t‐PA (0.6 mg/kg)	200	Japan	Direct mechanical thrombectomy was not noninferior	50 min	57 min for mechanical thrombectomy‐alone group, 58 min for combined group
DEVT 33	Noninferiority	−10%; 1‐sided α=0.025, power=0.8	t‐PA (0.9 mg/kg)	234	China	Direct mechanical thrombectomy was noninferior	61 min	101 min for mechanical thrombectomy‐alone group, 105 min for combined
MR CLEAN‐NO IV 34	Direct mechanical thrombectomy is superior	OR, 0.8; 2‐sided α=0.05, power=0.91	t‐PA (0.9 mg/kg)	540	Netherlands	Could not show superiority (primary), and could not show noninferiority (secondary)	31 min	63 min for mechanical thrombectomy‐alone group, 64 min for combined group
SWIFT‐DIRECT 35	Noninferiority	−12%	t‐PA (0.9 mg/kg)	404	Europe (2 Canadian centers)	Could not show noninferiority	55 min	75 min for mechnaical thrombectomy alone and 80 mins for combined group
DIRECT‐SAFE 36	Noninferiority	−10%	t‐PA (0.9 mg/kg)	780	Australia, China, Taiwan	Could not show noninferiority	64 min	87 min for mechnaical thrombectomy alone and 101 mins for combined group

DEVT indicates Direct Endovascular Thrombectomy vs Combined IVT and Endovascular Thrombectomy for Patients With Acute Large Vessel Occlusion in the Anterior Circulation; DIRECT‐MT, Direct Intra‐arterial Thrombectomy in Order to Revascularize AIS Patients With Large‐Vessel Occlusion Efficiently in Chinese Tertiary Hospitals: A Multicenter Randomized Clinical Trial; DIRECT‐SAFE, A Randomized Controlled Trial of DIRECT Endovascular Clot Retrieval Versus Standard Bridging Thrombolysis With Endovascular Clot Retrieval; MR CLEAN‐NO IV, Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands; OR, odds ratio; SKIP, Randomized Study of EVT With Versus Without Intravenous Recombinant Tissue‐Type Plasminogen Activator in Acute Stroke With ICA and M1 Occlusion; SWIFT‐DIRECT, Solitaire With the Intention For Thrombectomy Plus Intravenous t‐PA Versus DIRECT Solitaire Stent‐retriever Thrombectomy in Acute Anterior Circulation Stroke; and t‐PA, tissue‐type plasminogen activator.

Tenecteplase is a newer generation thrombolytic, which is more fibrin specific and used as single‐bolus dose, thus obviating the need of an infusion and transport physician in transfer patients. It is also known to have higher recanalization rates in the setting of an LVO. ⁴⁰ The results of the AcT (Alteplase Compared to Tenecteplase in Patients With Acute Ischemic Stroke) trial, a pragmatic large randomized controlled trial comparing alteplase and tenecteplase in patients with ischemic stroke presenting within 4.5 hours of symptom onset, demonstrated tenecteplase to be noninferior to alteplase. ⁴¹ These results have led to change guideline recommendations for hyperacute management of ischemic stroke in many countries. ⁴² , ⁴³ A recent mixed methods study after the revelation of results from bridging versus direct trials showed that 62.6% of respondents from 44 countries worldwide did not think there was sufficient evidence to withhold thrombolysis, and 60.7% of the participants chose to use tenecteplase over alteplase as the preferred drug for IVT if both drugs are backed by evidence. The focus group identified a need to better understand patient characteristics that may benefit from EVT‐only or combined strategies as well as the need for more data to inform physician decision‐making. The study strengthened the need for further studies using tenecteplase in such settings. ⁴⁴ Until now, there has been no direct head‐to‐head comparison between EVT alone versus EVT with bridging thrombolysis with tenecteplase for accessible LVO cases.

Review of Current Evidence: How much Longer can Patients with Stroke Tolerate LVO?

Whether to transfer a patient with suspected stroke directly to a remote CSC or first drop by a nearby IVT‐capable center has been a heated debate since early 2010, but even more so since the dawn of the EVT era. The discussion has evolved in lieu of the established efficacy of acute recanalization treatment, the resource‐demanding nature of the endovascular approach, and the accepted benefit of acute management in the dedicated stroke unit. In a few meta‐analyses, direct transfer to the CSC was summarized to provide better successful recanalization rates and lower hemorrhagic complications. ⁴⁵ However, these studies were exposed to selective reporting of excluding patients who remained at the local centers and selection bias of heterogeneous cases. The RACECAT (Transfer to the Closest Local Stroke Center vs Direct Transfer to Endovascular Stroke Center of Acute Stroke Patients With Suspected Large Vessel Occlusion in the Catalan Territory) trial was a multicenter cluster randomized trial to determine optimal transport strategy in patients with suspected LVO presenting to nonurban centers, which failed to show any significant difference in 90‐day neurological outcomes between transportation to a local stroke center versus an EVT‐capable center. ⁸ The essential issue behind the debates over drip‐and‐ship versus direct transfer would be the ischemic tolerance to LVO against time after onset/“total ischemia time” at a population level. It is a combination of the conditional probability dependent on the expected benefit of recanalization treatment modality, transfer time, transfer delay at the primary stroke center, and the expected rate of hemorrhagic complication with treatment. ⁹ If we take expected functional recovery and hemorrhagic complication subsequent to treatment modality somewhat consistent in qualified centers, the regional acute stroke care system should be organized according to how much longer patients with stroke can tolerate ischemic injury.

Current AMI treatment strategies are based on estimating hypothetical delays to PCI and between potential fibrinolysis and PCI. The more delay to PCI and the earlier fibrinolysis is administered relative to onset of pain, the higher the likelihood of benefit with early fibrinolysis. Learning from this and based on what we know from the stroke literature including results from the recent direct EVT trials ³¹ , ³² , ³³ , ³⁴ and RACECAT trial ⁸ , is it possible that similar strategies may be how treatment strategies are optimized in acute stroke? Is it that when the primary stroke center is closer and the CSC further away that IVT early is better? Is it that when the CSC is closer and endovascular access is easier that the direct EVT is best? We can make hypothetical estimates of these treatment effects with 1 of these 2 probabilities: (1) the benefit of thrombolysis will be preserved in the setting of delayed EVT (Figure 2A), or (2) there is no benefit of thrombolysis in the setting of either early or delayed EVT (Figure 2B). We need to develop such data to refine the stroke care system in a way that defines modes of patient presentation, components of ischemia, and reperfusion strategy selection along with a “strategy clock” similar to our cardiology colleagues based on evidence (Figures 3 and 4).

Figure 2.

Two potential relationships of time‐to‐treatment to thrombolysis benefit that might be observed in the setting of endovascular treatment (EVT): (A) showing preserved benefit of fast thrombolysis particularly in relation to the anticipated delay from thrombolysis to EVT (similar to the relationship seen in ST‐segment–elevation myocardial infarction), vs (B) showing no added benefit of fast thrombolysis in the setting of EVT, arguing against bridging therapy. cOR indicates common odds ratio.

Figure 3.

Modes of patient presentation, components of ischemia time, and flowchart for reperfusion strategy selection (times are arbitrary and need more evidence). LVO, large vessel occlusion; MSU, mobile stroke unit

Figure 4.

Maximum target times according to reperfusion strategy selection in patients presenting to a primary stroke center or comprehensive stroke center (CSC). LVO indicates large vessel occlusion.

Perspectives: Thrombolysis in the ERA of Thrombectomy

This review recapitulates the advancement of reperfusion strategies as well as the organization of transport systems in the management of AMI. It also highlights the need for such measures to be incorporated into systems of care for stroke, and further information is needed to develop efficient systems of care at a regional and hospital level.

These considerations may lead to the following recommendations:

• First, a regional stroke system needs to be organized to determine the best transport strategy on a case‐by‐case basis instead of routinely transporting the patients to the nearest hospital. The clinical presentation and potential treatment modality of patients with stroke, as well as the logistics and accessibility to the hospital should be considered.

• Second, in EVT eligible patients intravenous thrombolysis may be delayed until the condition is made that the benefit of intravenous treatment is higher than EVT, such as in cases with distal embolization after opening the main occlusion or recanalization failure.

• Third, tenecteplase should be considered as the thrombolytic of choice in such settings given its advantages over alteplase.

• To test these hypotheses, a randomized clinical trial deeply rooted in regional stroke systems is warranted.

Sources of Funding

The authors did not receive any funding.

Disclosures

The authors declare that there are no conflicts of interest.