Intravenous Thrombolysis in Acute Ischemic Stroke

Abstract

Acute ischemic stroke imposes significant morbidity and mortality on patients and proves costly for the society. The most common pathophysiology involves the obstruction of a cerebral arterial vessel with a thrombus leading to distal ischemia which unrelieved proceeds to infarction. Intravenous thrombolysis has emerged as an effective and safe strategy for reperfusion and has been shown to increase the odds of a long-term favorable outcome. For more than 2 decades, the mainstay of intravenous thrombolysis has been Alteplase. More recently however, Tenecteplase is increasingly incorporated into routine practice, and it has been shown to be superior to Alteplase for recanalization in patients with large vessel occlusion, and at least non-inferior in patients without large vessel occlusion. Newer studies have expanded the time windows, introduced “the tissue clock”, and included patients that were previously considered ineligible for thrombolysis, altogether increasing the pool of stroke patients with favorable outcomes.

1. Introduction

As of 2022, stroke is the leading cause of long-term disability in adults globally and is only second to ischemic heart disease as the leading cause of death in the world [1]. Eighty seven percentage of these strokes are ischemic, while the remaining 13% are hemorrhagic [2, 3]. The toll of a stroke on an individual is enormous, but it also proves costly for society. The cost associated with stroke in the United States alone between 2017 and 2018 was about $53 billion [3]. Further, while stroke was much more commoner in the elderly, the epidemiology has continued to shift towards earlier ages with up to a quarter of strokes now occurring in people of working age [4]. Before the advent of effective reperfusion strategies, the prognosis of acute ischemic stroke was much poorer. However, over the decades, advances in intravenous thrombolysis and endovascular therapies have drastically improved the outcomes for patients with acute ischemic strokes. Even with these therapies, rapid recognition and prompt treatment are essential to optimize benefits, limit disability, and reduce therapy-related adverse events. This chapter discusses intravenous thrombolytic agents, their efficacy and safety in acute therapy for ischemic strokes, and their use in special populations.

2. Background

2.1 Causes, risk factors, and clinical presentation of ischemic stroke

Ischemic stroke is defined as “an episode of neurological dysfunction caused by focal cerebral, spinal, or retinal infarction” [5]. Non-modifiable risk factors for ischemic stroke include increasing age, prior stroke, family history of stroke, and race (Black race, Hispanic, Chinese, and Japanese) [4]. Major modifiable risk factors for stroke include hypertension, tobacco use, diabetes, dyslipidemia, a sedentary lifestyle, and poor diet [6]. Ischemic stroke presents with focal or global neurologic deficits of a wide variety depending on the locus of ischemia. The hallmark of a typical stroke symptom is its acute onset which can involve any or a combination of deficits in motor, sensory, cranial nerve, visual field, gait, balance, speech and other cognitive functions. Brainstem strokes can also cause acute impairment in the level of consciousness.

2.2 Pathophysiology of ischemic stroke and endogenous fibrinolysis

The pathophysiology of ischemic stroke involves critical hypoperfusion of cerebral tissue due to the occlusion or stenosis of the supplying artery. Common mechanisms include lipohyalinosis of small vessels; an atherosclerotic large vessel disease (via hypoperfusion through a critical stenosis, local thrombus formation and occlusion, or thrombosis with distal embolization); embolization from aortic or cardiac sources; paradoxical embolization; vasculitis from primary or secondary CNS causes; hematologic disorders; other connective tissue and inflammatory disease among others. Most of these mechanisms result in a blood clot that blocks blood flow. Blood clots are composed of cross-linked fibrin, which traps blood cells. Neurons require a constant supply of oxygen and glucose to function properly. However, their susceptibility to hypoxia and low glucose varies. Within minutes of ischemia, ATP depletion leads to dysfunction of the neuronal sodium-potassium ATPase. This causes sodium to enter the cell accompanied by water, ultimately leading to cell death and swelling. Without intervention, it’s estimated that 1.9 million neurons and 14 billion synapses are lost irreparably every passing minute of stroke. This is equivalent to around 3.6 years of normal aging every hour [7].

The endogenous fibrinolytic mechanisms break cross-linked fibrin into fibrin degradation products. Circulating (and inactive) plasminogen is converted into plasmin (its active form) by the action of endogenous tissue plasminogen activator (tPA). The plasmin in turn is responsible for breaking down the cross-linked fibrin causing clot dissolution [8].

3. Thrombolysis in acute ischemic stroke

The endogenous process is limited in its speed and the scope of clot dissolution and is thus often not sufficient to prevent the rapid and permanent neuronal loss that characterizes ischemic strokes. Intravenous thrombolytic agents are designed to act more rapidly to convert circulating plasminogen into plasmin culminating in fibrinolysis. The introduction of intravenous thrombolytics (IVT) has been one of the most pivotal developments in the management of acute ischemic stroke. Several studies demonstrated that IVT use significantly improves functional outcomes in stroke patients [9, 10, 11].

3.1 Description of thrombolytic agents

Alteplase (recombinant tissue plasminogen activator or rtPA) is the recombinant form of the endogenous tissue plasminogen activator (tPA). Following the successful NINDS trial in 1995 showing improved outcomes in stroke patients, rtPA was approved by the Food and Drug Administration (FDA) for use within 3 h of onset of ischemic stroke symptoms [10, 12]. It is administered at a total dose of 0.9 mg/kg with a maximum dose of 90 mg. A dose of 0.6 mg/kg with a maximum of 60 mg is however studied and approved for use in Japan. 10% of the dose is given as a bolus while the remaining is administered as an infusion that runs for 1 h [8, 13]. Since 1996 and only until recently, rtPA has been the only intravenous thrombolytic used in acute ischemic stroke in standard clinical practice.

More recently, however, Tenecteplase (TNKase), a genetically modified form of rtPA has become studied extensively and is being used for acute stroke thrombolysis. It is an analog of rtPA with mutations at T103, N117, and K-H-R-R 296-299. TNKase is administered at a dose of 0.25 mg/kg with a maximum of 25 mg as a single bolus with the same indications, contraindications, and peri-thrombolytic care as rtPA. A higher dose of 0.4 mg/kg has been studied but found to be associated with a higher risk of symptomatic intracerebral hemorrhage [14]. TNKase has proven effective in the standard time window for rtPA and extended time windows are being studied [8].

TNKase holds many advantages over rtPA (Table 1). TNKase has a longer half-life of about 20 min compared to the 4 min of rtPA. This longer half-life is conferred by the former’s T103 and N117 mutations. The KHRR mutations at 269–299 confer on TNKase higher fibrin specificity and 80-fold resistance to Plasminogen Activator Inhibitor- 1 (PAI-1) leading to a reduced risk of systemic coagulopathy and a longer half-life respectively. TNKase is administered as a bolus without infusion, making it easier to administer. This is particularly advantageous to hospitals that utilize the ‘drip-and-ship’ workflow and need to transfer their patients to more advanced stroke centers. It eliminates the logistics of managing a thrombolytic infusion during transport [8]. It also eliminates the logistics of needing an IV line dedicated to infusion. It is not uncommon to have a delay between rtPA bolus and infusion which can cause the medication to fall below its therapeutic serum level without a re-bolus. This is not a factor in TNKase use [12]. Considering all costs incurred from admission to discharge, TNKase is also less costly than rtPA [15, 16].

	Alteplase (rtPA)	Tenecteplase (TNKase)
Pharmacokinetics and pharmacodynamics
Molecular structure	A recombinant form of the endogenous tissue plasminogen activator (tPA)	Genetically modified form of rtPA
Half-life	4 min	20 min
Fibrin specificity	Intermediate	High
Plasminogen Activator Inhibitor- 1 (PAI-1)	Low	Intermediate
Depletion of fibrinogen	Intermediate	Low
Dosage	0.9 mg/kg with a maximum dose of 90 mg. In Japan, 0.6 mg/kg with a maximum of 60 mg is approved for use	0.25 mg/kg with a maximum dose of 25 mg
Administration	10% of the dose as a bolus and the remainder as an infusion over 1 hour	Single bolus
Effectiveness
Successful recanalization in patients with large vessel occlusion who undergo EVT	Poor	Much better (3-fold higher)
Favorable functional outcome in patients with large vessel occlusion who undergo EVT	Good	2-fold higher
Early neurologic improvement	Possible	Higher chances
Favorable outcome and functional improvement in patients without large vessel occlusion	Good	Non-inferior
Safety
Symptomatic hemorrhagic transformation	Comparable	Comparable

Table 1.

Comparison between Alteplase and Tenecteplase.

Adapted from Zhu et al. [8].

TNKase is superior to rtPA in patients with large vessel occlusion and the 2019 AHA stroke guidelines recommend TNKase over rtPA in these patients [17]. When administered before endovascular thrombectomy, TNKase confers greater chances of post-thrombectomy reperfusion and better functional outcomes at 3 months without an increase in the risk of symptomatic hemorrhagic transformation [18, 19]. Pre-thrombectomy reperfusion is associated with a better prognosis. Alteplase has low pre-thrombectomy recanalization rates in patients with proximal large vessel occlusions. TNKase however demonstrates higher pre-thrombectomy reperfusion rates in these patients irrespective of the time between administration of the thrombolytic and imaging assessment of reperfusion [20].

In patients with ischemic stroke who have no large vessel occlusion or who have a large vessel occlusion and are ineligible for endovascular thrombectomy, TNKase has been shown by several studies to be non-inferior to rtPA [21, 22, 23].

In a 2022 systematic review encompassing 6 randomized controlled trials and a total of 1675 patients where the use of TNKase was compared with rtPA in patients presenting 4.5 h of last known well, TNKase showed clear advantages in both efficacy and safety. TNKase use was associated with more early neurologic improvement, better functional outcomes at 90 days as measured by the modified Rankin Score (mRS), and higher reperfusion rates and better outcomes in patients with large vessel occlusion. TNKase also did not show a higher bleeding risk than rtPA [15].

3.2 Eligibility for thrombolysis

Indications for IV thrombolytic use include disabling neurologic deficits attributable to stroke (including mild disabling symptoms or improving symptoms which nonetheless remain disabling), onset of symptoms or last known well within 4.5 h of presentation, diffusion-weighted imaging positive with FLAIR-negative strokes on MRI in patients who wake up with stroke symptoms.

Contraindications include mild-nondisabling symptoms, acute or prior history of intracranial hemorrhage, history of ischemic stroke within 3 months, history of ischemic stroke within 3 months, extensive regions of frank hypodensity on CT, uncontrollable blood pressure (systolic blood pressure >185 mmHg or diastolic blood pressure >110), severe head trauma within 3 months, intracranial/intraspinal surgery within 3 months, Gastrointestinal malignancy or bleeding within 21 days, acquired and inherited bleeding diathesis, suspected infective endocarditis, aortic arch dissection, intraparenchymal intracranial neoplasm.

Specific details on the indications and contraindications as well as nuances around some contraindications can be found in the AHA 2019 stroke guidelines. It is important to note that with additional studies since the original FDA approval of rtPA, many contraindications have become nuanced context-specific [9, 17].

3.3 Time windows for thrombolysis

The initial National Institute of Neurologic Disorders (NINDS) study in 1995 proved the efficacy and safety of rtPA in improving outcomes in selected stroke patients presenting within 3 h from the last known well or time of onset [11]. Subsequently, the ECASS III study showed that there was a benefit to some patients even within the 3–4.5 h window. The study excluded patients who were older than 80 years, had diabetes mellitus and prior stroke, had NIHSS ≥25, were taking oral anticoagulants, and those with CT evidence of early ischemic changes in >1/3 of the MCA territory. These additional criteria were thus (and are still used) to exclude patients in the 3–4.5 h window in practice [9]. More recent studies however have demonstrated that these additional exclusions did not confer an increased risk of bleeding [24] and it has become routine practice to uniformly expand the traditional window to 4.5 h based on the standard inclusion and exclusion criteria only.

With advances in imaging, there is increasing recognition that the window for reversibility of ischemic cerebral tissue greatly varies in individuals, and a “tissue clock” is becoming a stronger factor in eligibility for reperfusion therapies. It is estimated that 14–20% of strokes are ‘wake-up’ strokes with an unknown time of onset [25, 26]. The 4.5-h timeframe thus puts most of these patients outside the window even if the stroke had occurred just before waking up from sleep. Two pivotal studies showed that using imaging surrogates to estimate an approximate time of onset or to quantify the presence of salvageable ischemic tissue can lead to a safe and effective extension of the traditional time window.

In the WAKE-UP trial, patients with an unknown time of stroke onset, but had DWI-FLAIR mismatch (focal restricted diffusion on DWI without corresponding FLAIR hyperintensity) were randomized to rtPA versus placebo. This mismatch would suggest that the onset of their stroke was approximately 4.5 h or 6 h from onset. Compared to placebo, patients given tPA demonstrated a better 90-day functional outcome without a significant increase in symptomatic intracranial hemorrhage. Notably though, patients eligible for endovascular thrombectomy were excluded [27].

Similarly, another controlled trial, the EXTEND trial, showed that patients presenting within the 4.5 to 9-h window from the last known well (9 h from the midpoint of sleep for wake-up strokes), and showing a perfusion mismatch (hypoperfusion to ischemic core volume ratio ≥ 1.2; absolute difference of ≥10 ml; and ischemic core <70 ml) had better functional outcomes with rtPA compared to placebo. There was a significantly higher rate of symptomatic intracerebral hemorrhage in the rtPA group [28]. A systematic review and meta-analyses of these studies showed an overall functional benefit in these extended time windows which persisted when the increased bleeding rate was accounted for [29].

3.4 Time dependence of efficacy

While the time window for the efficacy of intravenous thrombolytics keeps expanding, it remains true that the benefit derived remains time-dependent with better outcomes seen with earlier administration [30]. Even with a “tissue clock”, the “time-is-brain” paradigm still holds. Faster administration is associated with lower odds of all-cause mortality and symptomatic intracranial hemorrhage and higher odds of long-term functional independence [31, 32, 33]. In recognition of this time-dependent benefit, institutional, regional, and national systems have been continuously optimizing their systems to achieve faster door-to-needle times while strengthening community and Emergency Medical Service systems for prompt recognition and transfer. For example, the American Heart Association (AHA) initiated the ‘Target: Stroke’ and has refined it over the years to provide hospitals and healthcare systems with the tools and incentives to achieve faster door-to-treatment (thrombolytic and endovascular thrombectomy) times. This initiative has been successful in achieving its objectives of faster treatment times and better outcomes [34, 35].

Mobile Stroke Units (MSU) as a system for prompt administration of IV thrombolytic have also emerged and are increasingly deployed in cities around the world. A mobile stroke unit is an ambulance with a CT scanner and trained staff who can respond rapidly to a stroke dispatch, identify stroke symptoms, perform the initial evaluation including the initial scans, and administer an IV thrombolytic on-site usually with the aid of remote consultation with a stroke provider, and triage to the appropriate stroke center [36, 37]. MSU has been shown in multiple studies to be associated with much faster thrombolytic times and better short-term and long-term functional outcomes. There is however a significant financial cost and the need to effectively integrate it into the existing locoregional system of stroke care [36, 38, 39].

4. Complications of intravenous thrombolysis

4.1 Hemorrhage

Intracerebral and systemic hemorrhage are known complications of intravenous thrombolytic use. Intracerebral hemorrhage ranges in severity from clinically insignificant to symptomatic intracerebral hemorrhage (sICH). While the NINDS definition of sICH is any hemorrhagic conversion associated with any neurologic worsening [11], the SITS-MOST definition specifies intraparenchymal hemorrhage with ≥4 points worsening in the National Institutes of Health Stroke Scale (NIHSS) score [40]. The incidence of the former is about 7% while that of the latter is about 2% [11, 40, 41]. The SITS-MOST definition is more commonly used in clinical practice as it often alters patient management [42].

Risk factors for hemorrhagic conversion include older age, higher body weight, baseline hypertension, atrial fibrillation, heart failure, kidney failure, current use of antiplatelets, extensive baseline white matter disease, high burden of baseline cerebral microbleeds, high blood pressure at presentation, higher clinical severity of stroke, extensive early changes or frank acute hypodensities on CT, acute and chronic hyperglycemia, and longer time from symptom onset to treatment [40, 43, 44, 45, 46, 47, 48, 49].

The AHA 2019 stroke guideline gives recommendations on treating thrombolytic-related sICH. If a patient develops symptoms of sICH within 24 h of IV thrombolytic use, the infusion should be stopped if still ongoing. Emergent CT head, CBC, PT/INR, PTT, fibrinogen level, and blood group and cross-match should be obtained. The first line therapy when available is 10 units of cryoprecipitate infused over 10–30 min. If the fibrinogen level was <150, additional doses should be given. When unavailable or the use of blood products is declined, 1 g of IV tranexamic acid given over 10 minutes, or 4–5 g of IV ε-aminocaproic acid given over 1 hour followed by 1 g until bleeding stops is recommended in place of cryoprecipitate. Hematology and neurosurgical consultations as well as supportive care should run concurrently [17].

4.2 Angioneurotic edema

Orolingual angioedema is also a known complication of IV thrombolytics. The incidence of angioedema with rtPA is about 1–5% [50]. The risk is higher in stroke patients who are on Angiotensin Converting Enzyme Inhibitors (ACE-I) [51, 52]. The manifestation and severity vary from unilateral tongue or lip swelling to bilateral swelling of oral structures to rapidly progressive oropharyngeal and laryngeal edema. Most cases are however overall mild, resolving within 24 h and not requiring the need to artificially secure the airway [50]. Management of IV thrombolytic-induced angioedema involves maintaining the airway, discontinuing the thrombolytic infusion, holding ACE-I, use of IV methylprednisone 125 mg, IV diphenhydramine 50 mg, and IV ranitidine 50 mg. In refractory cases, subcutaneous or nebulized epinephrine may be required. Supportive care should be provided concurrently [17].

5. Thrombolysis in special populations

5.1 Patients with premorbid disabilities or dementia

Patients with significant premorbid disabilities or dementia have been traditionally excluded from clinical trials for reperfusion therapies in stroke. The few observational studies have also shown higher morbidity and mortality leading to pessimism and widespread exclusion of these patients from IV thrombolysis and endovascular therapies in clinical practice. However, there is increasing recognition that treatment decisions in this population is complex and must align with patients’ goals while considering risks and benefits on a case-by-case basis. In the acute setting, it is better to avoid using fixed scales of premorbid disability as the cut-off for treatment or dichotomizing possible outcomes after treatment [53].

5.2 Patients with large vessel occlusion

The administration of intravenous thrombolytics (IVT) before endovascular thrombectomy (EVT) in patients with large vessel occlusion (the so-called ‘Bridging Therapy’) has been a subject of multiple studies. There had been conflicting results when comparing bridging Therapy (BT) with thrombectomy alone but the preponderance of the evidence, multiple metanalysis, and a real-world study are in favor of bridging therapy in improving functional outcomes [54, 55, 56, 57, 58, 59, 60, 61, 62, 63]. The current American and European guidelines support bridging therapy [17, 61, 64].

There are also important logistic considerations when considering skipping intravenous thrombolysis. Most centers that manage stroke patients are not capable of performing thrombectomies and thus must transfer patients with large vessel occlusions out for this procedure. The logistics of transportation and the distance to the receiving centers often introduce significant delays in obtaining EVT. All the while, without any intervention, the ischemic core continues to expand. It is also not uncommon that on arrival and rescreening at the receiving center, patients may no longer be candidates for EVT and would have passed the window for IVT. Therefore, bridging therapy is especially important for stroke centers unable to offer EVT.

5.3 Pregnant patients

Clinical trials on thrombolysis in stroke have excluded pregnant patients limiting the available data. Indeed, pregnancy was a relative contraindication to rtPA until recently [17, 65]. Altepase does not cross the placenta and it is not teratogenic. The concern is however for hemorrhagic complications including uterine bleeding [66]. The limited case series and reports have however shown IV rtPA to be overall reasonably safe in pregnancy [66, 67, 68]. The 2019 AHA stroke guideline gives a Class IIb recommendation to consider giving IV rtPA to pregnant patients with moderate to severe strokes if the benefit outweighs the potential risk of uterine bleeding [17]. This thus calls for considering each patient on a case-by-case basis considering multiple factors and taking well into account the risk of permanent disabling neurologic deficits without intervention.

6. Conclusion

Intravenous thrombolysis is proven to be effective and safe in the treatment of acute ischemic strokes with disabling symptoms in patients meeting the criteria. While rtPA had been the mainstay of intravenous thrombolysis, TNKase is increasingly being used: TNKase is superior in patients with large vessel occlusion and at least non-inferior in patients without large vessel occlusion. Early thrombolytic administration improves the chances of excellent functional outcomes. However, the time windows for eligibility have evolved to be more inclusive with advanced imaging. Likewise, the exclusion criteria have become less restrictive and more nuanced. In special populations, such as pregnant patients and those with significant baseline disabilities, a nuanced and individualized approach balancing risks and benefits should be used in determining eligibility.

Conflict of interest

The author declares no conflict of interest.