**3. Treatment of acute ischemic stroke**

#### **3.1 Introduction**

As discussed in the previous section, the prompt recognition of AIS using physical exam and its diagnosis using non-contrast CT (NCCT), CT-angiography (CTA), and CT Perfusion (CTP) is the first step in the efficient and effective management. In the last two decades, we have learned much about the treatment of AIS beginning with the concept of the "ischemic penumbra" to the use of thrombolysis in AIS and finally, to the revolutionary procedure of mechanical thrombectomy.

### **3.2 Principles of treatment**

As mentioned previously, there exists an ischemic penumbra in patients with AIS, tissue that is at risk but that has not yet infarcted. The primary goal of AIS management is to use interventions to recanalize the occluded artery and restore perfusion to the penumbra [38]. These interventions and these patients must be selected carefully to maximize benefit and avoid harm. In the following section, these interventions and the selection process will be discussed.

### **3.3 Thrombolysis**

One of the methods of recanalizing the occluded artery is by breaking up the thrombus using intravenous pharmacotherapy. Thrombi that occlude intracerebral arteries are created when the protein *fibrin* creates strands of protein that are long and insoluble [51]. The insoluble protein binds to platelets and the cross-linked fibrin forms a mesh over the platelet-protein complex forming a plug. Thrombolytic/ fibrinolytic drugs such as alteplase, or tissue-plasminogen activator (tPA) cleave the inactive protein plasminogen into its active form plasmin. Plasmin degrades the fibrin matrix that was reinforcing the thrombus, thereby allowing clot break down and recanalization. In 1995, the landmark NINDS trial [15] demonstrated that patients with AIS that received tPA within 3 hours of patient LKNT had a significantly higher likelihood of favorable outcome (39%) at 3 month follow-up compared to those who received placebo (26%) as measured by the Modified Rankin Scale (Odds ratio: 1.7). However, there was also a significantly higher risk of symptomatic intracerebral hemorrhage (ICH; **Table 3**) in the tPA group (6.4%) versus the placebo group (0.6%). It was not until 2008 "European Cooperative Acute Stroke Study" (ECASS) III trial [52], that the tPA window was extended to 4.5 hours. A subsequent systematic review of four clinical trials investigating thrombolysis [55] determined that, as the time to symptom onset increases, the benefit from tPA declines and the risk of mortality increases. Beyond the 4.5 hour window, the risk of tPA outweighs the benefits (**Figure 4**). In a metanalysis of 6756 patients from nine studies [56], the authors found that patients who received tPA and a 5.55% increase in absolute risk of parenchymal type II hematoma [54] (Odds ratio: 5.55), 3.1% increase in absolute risk of SITS-MOST ICH (Odds ratio: 6.67), and 2.3% increase in absolute risk of fatal ICH (Odds ratio: 7.14). One of the main caveats of thrombolysis is that the clinician *must know* the patient's LKNT. There are a significant proportion of patients that in whom the time of symptom onset is unknown. Traditionally, these patients would not be candidates for thrombolysis as the benefit-to-risk ratio would not be known. However, the landmark WAKE-UP trial, investigated the use of thrombolysis in this

*Diagnosis and Management of Acute Ischemic Stroke DOI: http://dx.doi.org/10.5772/intechopen.106389*


#### **Table 3.**

*Different definitions of symptomatic ICH depending on clinical trial [47]. The NINDS trial used the most liberal definition, explaining the higher estimates of ICH compared to what was reported in subsequent studies.*

group of patients [47]. The authors used MRI with diffusion to determine if there was still a significant volume of penumbra and mismatch, and in carefully selected patients, thrombolysis was administered. There was a greater likelihood of favorable outcome in patients administered tPA (53.3%) versus those who received placebo (41.8%) at 3 months (Odds ratio: 1.61). In the DIAS trial, the authors used a highly fibrin-specific thrombolytic agent, desmoteplase, in patients presenting with AIS [57]. The patients presented between 3 and 9 hours from LKNT and were carefully selected by use of MRI to determine who would be a good candidate for thrombolysis. A higher rate of reperfusion and favorable outcome was seen in patients who were given thrombolysis (71.4% and 60.0%) compared with those who received placebo (19.2% and 22.2%). Therefore, if a center does have MRI capabilities, carefully selected patients with AIS with unknown time of symptom onset may be candidates for thrombolysis.

**Table 4** shows the indications and contraindications for thrombolysis for patients presenting with AIS [7]. The only *absolute* contraindication to administration of thrombolysis is demonstration of ICH on NCCT. The other criteria listed are relative and are dependent on the clinical situation. For a patient to be a candidate for thrombolysis, the stroke should be classified as clinically disabling, usually referring to a NIHSS>52 . The "Phase IIIB, Double-Blind, Multicenter Study to Evaluate the Efficacy and Safety of Alteplase in Patients With Mild Stroke: Rapidly Improving Symptoms and Minor Neurologic Deficits" (PRISMS) trial compared administration of tPA to aspirin in patients with AIS presenting with a NIHSS≤5 and determined that there was no significant difference in favorable outcome at 3 months [58].

Once it is determined that a patient is a candidate for thrombolysis, the dosing should be calculated, and formulation prepared. The dose that is primarily used for AIS is 0.9 mg/kg of patient's ideal body weight, with a maximum dose of 90 mg [7]. Of the total dose, 10% is administered as a bolus over 1 minute and the remainder as an infusion over 60 minutes. The ENCHANTED trial investigated a lower dose of tPA, 0.6 mg/kg in a cohort of Asian patients presenting with AIS and although they demonstrated a lower risk of ICH compared to standard dose (1% vs. 2.1%), the trial was not able to show noninferiority of the lower dose with respect to death or disability at 3 months [59]. While alteplase is standard of care for thrombolysis in AIS, in the last 10 years, there is evidence suggesting that tenecteplase (TNK) the

<sup>2</sup> While NIHSS >5 is usually used as the standard for clinically disabling, there are exceptions to this. For example, a patient presenting with AIHS who demonstrates global aphasia would have a NIHSS of 4. However, this would be significantly disabling for the patient and therefore, he would likely qualify for thrombolysis.


#### **Table 4.**

*Indications and contraindications for tPA [7]. Importantly, the only absolute contraindication to tPA use is intracerebral hemorrhage on noncontrast CT. The rest are dependent on the clinical scenario.*

medication used in thrombolysis for acute myocardial infarctions, is as safe and at least as effective as tPA [60–62]. The primary advantages to TNK would be its longer half-life, eliminating the need for a 60 minute infusion, and its greater specificity for fibrin, which could mean more effective thrombolysis [2]. There are currently largescale clinical trials underway to determine the non-inferiority of TNK compared to tPA (NOR-TEST) and efficacy and safety of TNK in patients presenting more than 4.5 hours since LKNT (TIMELESS), and in patients with basilar artery occlusions (POST-ETERNAL). In the next 10 years, TNK may indeed be the standard of practice.

There are two primary complications that can occur from thrombolysis administration in the acute phase. The first is angioedema and this might occur minutes to hours after administration of tPA [51]. As mentioned earlier, tPA cleaves plasminogen into its active form plasmin. Plasmin activates complement as well as the kinin pathways which leads to an inflammatory response and an increase in systemic cytokines. Therefore, it should not be surprising that one of the consequences of tPA administration is angioedema, an acute albeit transient swelling of deeper layers of the skin and mucosa. The swelling is red and well-circumscribed and usually involves the orolingual, periorbital, and pharyngeal regions. Angioedema is seen in approximately 5% of patients who receive tPA and is usually mild and patients who are on ACE inhibitors are at higher risk [63]. These patients require careful monitoring as if the swelling becomes severe and involves the airway, the patient may need intubation. Usually the angioedema is mild and self-resolves after the tPA infusion is complete. The signs and symptoms of the reaction can be managed by IV diphenhydramine and/or ranitidine histamine (H1) receptor antagonists [64].

The second major complication of tPA administration, which was alluded to earlier, is ICH. ICH can occur in up to 7% of tPA administrations and can be associated with up to 83% mortality [65]. Patients must be counseled about this increased risk to make an informed decision about receiving tPA and clinicians should be aware of the risk of ICH to recognize and manage it promptly. The factors associated with a higher risk of ICH include larger volume of hypoperfused tissue, larger established infarct, higher NIHSS, and higher glucose and/or blood pressure at the time of tPA

*Diagnosis and Management of Acute Ischemic Stroke DOI: http://dx.doi.org/10.5772/intechopen.106389*

administration [64, 66]. Therefore, patients who receive tPA must have their systolic blood pressure kept below 185mmg and be euglycemic. In *all* patients who receive tPA, a NCCT should be repeated 24 hours post-administration. Even if a patient does not have a hemorrhage large enough to cause clinical deficits or change in level of consciousness, the size and location of the ICH will influence future decisions about secondary stroke prevention. The clinician should have a low threshold to order a stat repeat NCCT earlier than 24 hours if there is a clinical deterioration of the patient.

In summary, tPA is an effective tool in the management of AIS in carefully selected patients in whom the benefits of thrombolysis outweigh the risk of hemorrhage. Unfortunately, a significant number of patients present with AIS outside of the 4.5 hour window or meeting another contraindication to tPA. In 2015, a new hope of treatment emerged for these patients.

#### **3.4 Endovascular thrombectomy**

While thrombolysis is effective for a select group of patients, it is accompanied by several limitations. First, given that this is a systemic fibrinolytic medication, it is accompanied with the risk of bleeding anywhere in the body, especially in the brain. Second, only select patients qualify for its administration. Third, the rate of recanalization for proximal, large-vessel occlusions (LVOs) is poor, ranging from 13–50% [2, 67]. These are dense clots that are in the major arteries in the brain (the terminus of the internal carotid artery, the early branches of middle cerebral artery (MCA; M1, M2), and the basilar artery), even though these occlusions make up at least one-third of strokes [67] and can cause significant disability.

These three disadvantages are not shared by the endovascular thrombectomy (EVT) procedure. In this procedure, a patient is taken to interventional neuroradiology suite, IV contrast is administered to the patient which sequential x-rays of the head and neck are obtained. An occlusion is localized when it is evident that there an abrupt

#### **Figure 5.**

*MRI of patient with acute right middle cerebral artery stroke with DWI on the left and FLAIR on the right. In the DWI image, the white circle marks an area of diffusion restriction indicating acute ischemia. However, there are minimal to no changes in the corresponding FLAIR image. This indicates that a significant core has not yet formed yet and mismatch exists.*

halt of contrast filling the artery. A catheter attached to a wire is inserted into the femoral artery and advanced until it reaches the clot, which can then be aspirated or retrieved using a stent (**Figure 5**). The first trials to examine the benefit of EVT were performed in 2013 and did not show the procedure to be clinically efficacious [2]. This changed with the advent of new methods of imaging and better catheters and in 2015, the "Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands" (MR CLEAN) trial demonstrated that patients that received EVT within 6 hours of symptom onset were more likely to achieve functional independence at 3 months (32.6%) compared to those who received placebo (19.1%) [68]. Other trials confirmed the findings of MR CLEAN and thus emerged new guidelines for the eligibility for EVT: **1) patients ≥ 18** who presented **2) within 6 hours of symptom onset** with a **3) LVO,** a **4) NIHSS ≥ 6**

and an **5) ASPECTS score of CT ≥ 6 on NCCT** [7]. With the introduction of CTP, clinicians could identify core and penumbra in patients with AIS and determine which patients could still benefit from intervention. In the subsequent AURORA, DEFUSE 3 and DAWN trials, it was determined that EVT could be safe and effective in patients presenting up to 24 hours post symptom onset [69–71]. However, if a patient presents outside of the initial six-hour window, they must receive a CT perfusion or MRI with DWI to determine the volume of core infarct that exists and if there is still mismatch; otherwise it will be impossible to determine if the patient could benefit from the procedure. As mentioned earlier, there are specific CTP criteria that allow a patient to be eligible for EVT if they present outside of the initial 6 hour window. The MMR must be greater than 1.8, the penumbra must be greater than 15 mL, and the Tmax >10 seconds [41]. The HERMES meta-analysis of five EVT trials found that patients who received standard of care without EVT had a 14% higher absolute risk of not having a favorable outcome compared to those who received EVT. There was no significant difference in symptomatic hemorrhage between groups. Therefore, it is now standard of care to consider each patient who presents within 24 hours with a proximal LVO for EVT [72].

Unfortunately, not all AIS patients are eligible for EVT. The patient must have a proximal LVO to be accessible by the current clot-retrieval tools. As clots become more distal, there is a lower likelihood of successful procedure and higher likelihood of complications. While experienced interventionalists may go after clots in the basilar artery, anterior cerebral arteries, and distal middle cerebral arteries, there is little evidence to suggest the efficacy of these procedures. Second, not all AIS patients have access to EVT. The intervention is only offered at major, tertiary care centers. While thrombolysis can be done even in remote settings with neurologists guiding the treatment via "telestroke", for EVT a patient needs to be transferred, often over hundreds of kilometers, to obtain the procedure and by the time they reach the EVT site, there may be no penumbra left [2].

EVT is also accompanied by its own risks [73]. While ICH is more common with tPA, there is still a risk of hemorrhagic transformation with EVT as causing reperfusion to already infarcted tissue can cause injury, edema, and resulting hemorrhage. As this is an interventional procedure, there is always the risk of infection or clot developing at the site of entry. When the interventionalist is trying to access the occlusion, pieces of the clot can break off and move distally creating occlusions not accessible by the catheter. In rare cases, arteries can be damaged or even ruptured from the catheter itself.

Despite the disadvantages to EVT, it remains at the forefront of AIS therapy. The advent of EVT has revolutionized stroke protocols and care across the world with the acute stroke window being extended from a mere 4.5 to an entire day.


#### **Table 5.**

*Factors that would favor EVT alone (top) vs. factors that favor tPA and EVT strategy (bottom).*

Given the advantages of EVT, the question arises of whether patients with LVO should go straight for EVT or if they would benefit from tPA administration first. There have been multiple trials that have compared the use of EVT alone to EVT combined with thrombolysis and have yielded mixed results. The "Multicenter Randomized Clinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands-NO IV" (MR-CLEAN-NO IV) [74] and "Randomized study of endovascular therapy with versus without intravenous tissue plasminogen activator in acute stroke with ICA and M1 occlusion" (SKIP) trials [75] did not demonstrate noninferiority of EVT alone compared to EVT and tPA whereas the DIRECT MT [76] and DEVT trials [77] demonstrated that EVT alone was indeed noninferior. The different results of the studies may have been due to different characteristics of the study population or of the study design itself. For example, in the DEVT trial, the population had a higher proportion of patients with intracranial atherosclerosis which can change the benefit obtained with thrombolysis. There is currently not enough evidence to suggest a strategy of EVT alone for patients presenting with AIS who have LVOs. It is necessary to determine if there is a particular subgroup that would benefit from EVT alone [78]. For example, according to DIRECT MT and MR-CLEAN-NOIV, patients with tandem occlusions (simultaneous blockage of both internal carotid artery and middle cerebral artery) may benefit from EVT alone. Patients with large ischemic cores who receive EVT alone may also have decreased likelihood of symptomatic ICH as per all of the trials except MR-CLEAN-NOIV. At the same time, taking the time to select these patient subgroups in a clinical scenario may be detrimental to those who would benefit from both EVT and tPA. **Table 5** illustrates the specific factors that could favor an EVT alone strategy as well as factors that would favor a thrombolysis and EVT strategy [79]. As per current guidelines, patients presenting with LVO not meeting the contraindications to thrombolysis should receive thrombolysis as long as it *does not delay the patient receiving EVT* (**Figures 6** and **7**) [7].

#### **3.5 Post-acute care**

In the acute window, in patients who receive intervention or have a very large infarct, it is essential to monitor heart rate and blood pressure every 15 minutes for

#### **Figure 6.**

*Relationship between time of symptom onset to tPA administration to likelihood of symptomatic ICH (blue line; left axis) and likelihood of good outcome (green line; right axis). As is evident, with increasing time, the risk of symptomatic ICH increases and the likelihood of good outcome decreases. Importantly, beyond 270 minutes there is still a higher likelihood of ICH but no significant difference in good outcome.* **\****no significant difference between treatment and placebo. (adapted from Lees et al. [55]).*

#### **Figure 7.**

*Radiograph of proximal M1 occlusion pre (left) and post (right) EVT procedure. An 81 year old female presented with acute left sided weakness and complete neglect of the left side of space. Her CT angiogram demonstrated an occlusion on the proximal M1 branch of the MCA and she was sent to the interventional neuroradiology suite. The figure on the left demonstrates no contrast filling the branches of the MCA distal to the clot (arrow). After thrombectomy, the artery is recanalized and there is anterograde flow (right).*

2 hours, every 30 minutes for 6 hours, and every 60 minutes until 24 hours after starting treatment [80]. It is also pertinent to monitor the patients "neurovitals" their level of consciousness, strength, and language to ensure their clinical status is not deteriorating. As previously discussed, there should be a low threshold for repeating a NCCT in the acute period. Patients with AIS should also be kept NPO until their swallowing is assessed formally as their decreased level of consciousness and facial weakness can increase the likelihood of aspiration. All stroke patients who receive tPA, EVT, or who present with significant deficits, should be admitted to a dedicated stroke unit where

*Diagnosis and Management of Acute Ischemic Stroke DOI: http://dx.doi.org/10.5772/intechopen.106389*

they can be monitored closely by stroke specialists and an interdisciplinary team of nurses, physiotherapists, speech and language pathologists, and dieticians to ensure favorable functional outcome. Evidence suggests that patients that are cared for at an acute stroke unit have less likelihood of disability and mortality compared to those that are admitted to a general ward [81]. Early rehabilitation is crucial in preventing long-term disability and early management of blood pressure, diabetes, cholesterol, and antiplatelet/anticoagulant therapy is crucial in the secondary prevention of stroke.
