Activase^® is proven to reduce disability at 90 days in patients treated within 3 hours of symptom onset⁶

Amir Hassan: 00:04

Hello everyone. My name is Dr. Amir Hassan and I am an interventional stroke neurologist. Today, I'll talk about optimizing care for patients with acute ischemic stroke. Before I get started, I need to provide some disclosures. This program is presented on behalf of Genentech and the information presented is consistent with FDA guidelines. I have been compensated by Genentech to serve as a speaker for this program. This program is intended to provide general information about Activase and not medical advice for any particular patient. Any adverse events included in this presentation today have been reported to Genentech drug safety, and no action is required by any member of the audience. This program may be monitored by Genentech for adherence to program requirements. All materials are the property of Genentech and may not be recorded, photographed, copied, or reproduced. Today, I will review the diagnosis of acute ischemic stroke, including brain imaging, discuss what is needed to determine Activase eligibility and outline some recommendations to enhance the efficiency of your stroke program and make the process faster. First, I need to provide some important safety information about Activase.

Announcer: 01:06

Activase (alteplase) is indicated for the treatment of acute ischemic stroke. Exclude intracranial hemorrhage as the primary cause of stroke signs and symptoms, prior to initiation of treatment. Initiate treatment as soon as possible but within 3 hours after symptom onset. Do not administer Activase to treat acute ischemic stroke in the following situations in which the risk of bleeding is greater than the potential benefit: current intracranial hemorrhage, subarachnoid hemorrhage, active internal bleeding, recent (within 3 months) intracranial or intraspinal surgery or serious head trauma, presence of intracranial conditions that may increase the risk of bleeding (for example, some neoplasms, arteriovenous malformations, or aneurysms), bleeding diathesis, current severe uncontrolled hypertension.

Amir Hassan: 01:59

Today's talk will be framed around the hypothetical case study of Mary, a 45-year-old Caucasian woman. She was found slumped over in a cubicle at a university library at 2:50 PM. EMS was on the scene at 3:00 PM. They found the patient was conscious; determined she was last known well 30 minutes earlier. Mary presented with slurred speech, incoherent speech, left facial droop, and a right gaze preference, which was probably due to a visual field cut on the left. She also had weakness of the left arm and leg. Based on this information, EMS suspected a stroke.

Amir Hassan: 02:30

So how can we provide Mary with the best possible care? As we are all aware, for patients with acute ischemic stroke, each minute counts. Without medical management, a stroke patient loses an estimated 1.9 million neurons a minute. This ages the brain by just over 3 weeks, every minute. So, it is imperative to act quickly when a stroke is suspected. Let's consider what the routing considerations are for a patient with a suspected stroke.

Amir Hassan: 02:55

In its 2019 guidelines, the American Heart Association/American Stroke Association recommends that patients with a positive stroke screen or who strongly suspected to have a stroke should be transported rapidly to the closest healthcare facilities that are able to administer IV alteplase.

Amir Hassan: 03:13

In addition, the American Heart Association/American Stroke Association Mission: Lifeline^® Stroke committee, published an algorithm for routing in 2017. And that was devised for patients who have a suspected large vessel occlusion. They recommend that patients should be taken directly to the nearest comprehensive stroke center, which may not be the closest stroke center, if transport to this facility takes less than or equal to 15 minutes and does not preclude the use of Activase. Remember, Activase administration should occur soon as possible, but within 3 hours after symptom onset. If transport to the nearest comprehensive stroke center adds more than 15 minutes to your transfer time, or if transport to this facility precludes the use of Activase, the patient should be transported to the nearest stroke center. Patients that are suspected by EMS to have had a stroke but not a large vessel occlusion, should be taken to the nearest stroke center. Remember, these are only recommendations. Ultimately, all routing decisions should conform to regional policies. Now let's return to our case.

Amir Hassan: 04:12

The closest stroke center was a primary stroke center which, was 10 minutes away. The nearest comprehensive stroke center was 30 minutes away. So, in accordance with regional protocols, EMS transported Mary to the primary stroke center. They arrived 45 minutes after she was last known well. So, what do we need to do to diagnose and determine an appropriate treatment for Mary? You need to establish the time the patient was last known well, which EMS can help obtain. In order to accurately diagnose acute ischemic stroke, it is recommended that you obtain the patient's history. It is important to know if the patient was functional beforehand. You should perform a disability assessment, measure stroke severity, and measure the patient's blood pressure and blood glucose concentration. You may also need to send the patient for imaging to look for an intracranial hemorrhage. In addition, you might also consider obtaining blood coagulation measurements, as well as ordering imaging to confirm the large vessel occlusion, if suspected. Imaging can also be performed to determine infarct core size and penumbra size. Now, let's consider imaging for patients with a suspected stroke.

Amir Hassan: 05:16

Here are Mary's CT scan results. CT can be used to detect an intracranial hemorrhage, which appears as a hyperdense region, as well as subarachnoid hemorrhage, which is more diffused. CT may also reveal signs of ischemia, which appears as a hypodense area. Tools are available to help identify areas of hypoattenuation. In the NINDS trial, almost one third of patients with acute ischemic stroke had early ischemic signs. These patients had a high probability of having infarct on follow up. A hypodense artery sign may indicate an acute thromboembolism. Mary's CT scan results show no evidence of any bleeding or early ischemic signs.

Amir Hassan: 05:52

Should we consider anything else before determining treatment? It is important to have a conversation with the patient or their caregiver about disability. Each neurological deficit present at the time of the treatment decision should be considered in a context of individual risk and benefit. How do we define a disabling deficit? Activase clinical trials enrolled patients with a measurable neurological deficit, which was defined as an impairment of language, motor function, cognition, gaze, vision, or neglect. The American Heart Association/American Stroke Association considers the following deficits to be disabling: Complete hemianopsia, severe aphasia, visual or sensory extinction, any weakness limiting sustained effort against gravity, any deficits that lead to a total in NIH Stroke Scale greater than 5, any remaining deficit the patient or practitioner considers potentially disabling. Here are 2 instances from my practice when I had to use my own clinical judgment to determine if a specific deficit was disabling. These examples may not be representative of patients that you see in your own clinical practice.

Amir Hassan: 06:56

The first is a construction worker who was unable to grasp an object with his left hand due to weakness, despite being able to lift his left arm. He might have been unable to work in construction again, so I considered his left hand weakness a disabling deficit. The second is a newscaster who had mild to moderate aphasia and was unable to speak without slurring. She might have been unable to speak clearly in the front of the camera again. So, I considered her aphasia to be a disabling deficit. Hence, clinical judgment is required when determining if a deficit is disabling, irrespective of the NIH Stroke Scale score for that deficit. Activase is an integral part of acute ischemic stroke care and is the standard of care.

Amir Hassan: 07:35

In its 2015 and 2019 guidelines the American Heart Association/American Stroke Association recommends Activase for selected patients who may be treated within 3 hours of onset of acute ischemic stroke, including those eligible for subsequent mechanical thrombectomy.

Amir Hassan: 07:51

Let's review more of the important safety information for Activase. There are warnings and precautions for the treatment of acute ischemic stroke with Activase, in the following areas: bleeding, hypersensitivity, thromboembolism, cholesterol embolization, and coagulation tests, which may be unreliable during Activase therapy. There are also adverse reactions associated with Activase. Now we'll take a closer look at each one.

Announcer: 08:16

Activase can cause significant, sometimes fatal internal or external bleeding, especially at arterial and venous puncture sites. Avoid intramuscular injections and trauma to the patient. Perform venipunctures carefully and only as required. Fatal cases of hemorrhage associated with traumatic intubation in patients administered Activase have been reported. The concomitant administration of heparin and aspirin with and following infusions of Activase for the treatment of AIS during the first 24 hours after symptom onset has not been investigated. Because heparin, aspirin, or Activase may cause bleeding complications, carefully monitor for bleeding, especially at arterial puncture sites. Hemorrhage can occur 1 or more days after administration of Activase, while patients are still receiving anticoagulant therapy. If serious bleeding occurs, terminate the Activase infusion and treat properly.

Announcer: 09:13

In the following conditions, the risks of bleeding with Activase are increased and should be weighed against the anticipated benefits: recent major surgery or procedure, cerebrovascular disease, recent intracranial hemorrhage, recent gastrointestinal or genitourinary bleeding, recent trauma, hypertension, acute pericarditis, subacute bacterial endocarditis, hemostatic defects including those secondary to severe hepatic or renal disease, significant hepatic dysfunction, pregnancy, diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions, septic thrombophlebitis or occluded AV cannula at seriously infected site, advanced age, patients currently receiving oral anticoagulants or any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location.

Announcer: 10:14

Hypersensitivity, including urticarial, anaphylactic reactions, have been reported after administration of Activase. Rare fatal outcome for hypersensitivity was reported. Angioedema has been observed during and up to 2 hours after infusion in patients treated for acute ischemic stroke and acute myocardial infarction. In many cases, patients received concomitant angiotensin-converting enzyme inhibitors. Monitor patients during and for several hours after infusion for hypersensitivity. If signs of hypersensitivity occur, eg, anaphylactoid reaction or angioedema develops, discontinue the Activase infusion and promptly institute appropriate therapy, eg, antihistamines, intravenous corticosteroids, epinephrine. The use of thrombolytics can increase the risk of thrombo-embolic events in patients with high likelihood of left heart thrombus, such as patients with mitral stenosis or atrial fibrillation. Activase has not been shown to treat adequately underlying deep vein thrombosis in patients with PE. Consider the possible risk of re-embolization due to the lysis of underlying deep venous thrombi in this setting.

Announcer: 11:27

Cholesterol embolism, sometimes fatal, has been reported rarely in patients treated with thrombolytic agents; the true incidence is unknown. It is associated with invasive vascular procedures, eg, cardiac catheterization, angiography, vascular surgery, and/or anticoagulant therapy. Coagulation tests and/or measures of fibrinolytic activity may be unreliable during Activase therapy unless specific precautions are taken to prevent in vitro artifacts. When present in blood at pharmacologic concentrations, Activase remains active under in vitro conditions, which can result in degradation of fibrinogen in blood samples removed for analysis. The most frequent adverse reaction associated with Activase acute ischemic stroke therapy is bleeding.

Amir Hassan: 12:16

Back to our case study. Mary has no significant medical history. She was last known well 90 minutes ago. She has deficits that are considered disabling. Her NIH Stroke Scale score was 10. Her blood pressure, blood glucose concentration, blood coagulation results, and CT scan results were all within normal limits. A large vessel occlusion was suspected but was not yet confirmed at this point in her treatment journey. Mary's physician concluded that she had an acute ischemic stroke and that there were no contraindications to Activase treatment. Let's examine the pivotal clinical trial for Activase.

Amir Hassan: 12:51

It was a 2-part, placebo controlled, double blind clinical trial. Patients could be included in the NINDS trial if they had an acute ischemic stroke with a defined time of onset that allowed for treatment within 3 hours, a deficit measurable on the NIH Stroke Scale, and a baseline CT scan showing no evidence of intracranial hemorrhage. Part 1 of the NINDS trial assessed the changes in neurologic deficits 24 hours after stroke onset. Part 2 used 4 assessment scales that represent different aspects of recovery from stroke measured 3 months after stroke. Favorable outcome was considered to be: an NIH Stroke Scale score of 1 or less, a Modified Rankin Scale score of 1 or less, a Barthel Index score of 95 or greater, and a Glasgow Outcome Scale score of 1. Results from part 2 of the NINDS trial showed across all 4 stroke assessment scales, more patients who were treated with Activase had minimal or no disability at 3 months compared to patients who were treated with placebo. When we look at the Modified Rankin Scale, there was a relative increase of 48% from the placebo to Activase arm. A Modified Rankin Scale score of 0 or 1 was considered a favorable outcome in this trial.

Amir Hassan: 14:01

Taking into consideration the results from all four scales, the global odds ratio for a favorable outcome at 90 days with Activase was 1.7. In part 1 of the NINDS trial, there are no significant differences in the primary outcome between patients who were treated with Activase or placebo at 24 hours after stroke onset. There are risks associated with using Activase, including symptomatic intracranial hemorrhage and possibly death. The symptomatic hemorrhage rate at 36 hours was 0.6% in the placebo arm and 6.4% in the Activase arm, a significant difference. The total, that is both of symptomatic and asymptomatic, intracranial hemorrhage rate for all time periods examined was 6.4% in the placebo arm and 15.4% in the Activase arm, also a significant difference. The new ischemic stroke rate within the first 3 months was 5.4% in the placebo arm and 5.8% in the Activase arm. A nonsignificant difference. All-cause mortality at 90 days was 20.5% in the placebo arm and slightly lower, 17.3%, in the Activase arm.

Amir Hassan: 15:05

So, returning to the case study, I think you'd agree that Mary was eligible for Activase treatment. The recommended dose of Activase is 0.9 milligrams per kilogram. 10% of the total dose is administered as initial intravenous bolus over 1 minute. The remaining 90% is infused intravenously over 60 minutes. The total dose must not exceed 90 milligrams. Mary's Activase treatment was initiated 1 hour and 35 minutes after she was confirmed last known well. The door-to-needle time was 50 minutes. Due to her NIH Stroke Scale score of 10 and disabling deficits, her physician suspected she had a large vessel occlusion, which needed to be confirmed using imaging.

Amir Hassan: 15:44

What are the protocols at your institution for advanced imaging after CT has been performed? At my institution, a CTA typically directly follows a CT scan. The patient begins treatment with Activase concurrently. The patient never leaves a CT table, which has helped us achieve our door-to-needle goal of 45 minutes. Different imaging modalities have advantages and limitations. CT may detect an intracranial hemorrhage and the infarct core. It is inexpensive and widely available. However, patients are exposed to ionizing radiation, and it has limited sensitivity compared to MRI, which may detect an intracranial hemorrhage and infarct core. However, an MRI is more expensive, time consuming, and is generally less readily available. CTA and MRA can be used for arterial imaging. CTA is highly specific and highly sensitive, but the iodinated contrast agent may lead to nephropathy. MRA does not require contrast medium but may overestimate the degree of stenosis. CT and MR perfusion may distinguish the infract core from the penumbra. CT perfusion is rapid and quantitative, but techniques are not standardized. MR perfusion has noncontrast alternatives available, but like CT perfusion, postprocessing techniques are not standardized.

Amir Hassan: 16:54

Shown here are Mary's CTA scan results. CTA can be used to pinpoint the site of occlusion, provide details of the collateral circulation, identify tandem occlusions or stenosis, and document the arterial anatomy. Collateral circulation varies from person to person and has been correlated with infarct growth and functional recovery. Mary's CTA results show she had a large vessel occlusion. At this stage, Mary's physician was able to make some decisions about additional treatment. Mary had an acute ischemic stroke from a right middle cerebral artery occlusion. She was last known well 2 hours ago and was 30 minutes into her Activase treatment. She was considered a candidate for mechanical thrombectomy and was prepared for transport to another facility to receive this procedure. Think about what the protocols are for interfacility transport of patients, like Mary, at your institution.

Amir Hassan: 17:42

In follow up, we learned that Mary arrived at the mechanical-thrombectomy-capable center within 40 minutes, 2 hours and 40 minutes after she was last known well. Her Activase infusion was completed on arrival, and she showed no signs of neurological deterioration, hypertension, hypersensitivity, or bleeding. The neurointerventionalist deemed her eligible for mechanical thrombectomy. Mary was continually monitored for neurological deterioration, hypertension, and hypersensitivity. What opportunities are there to improve the time to treatment?

Amir Hassan: 18:13

Multiple parallel processes can help expedite treatment for patients with acute ischemic stroke, who are eligible for Activase, with or without subsequent mechanical thrombectomy. Let's take a look at an example of a stroke treatment pathway with parallel processes. Once the patient arrives at the hospital, the stroke team and ED staff can evaluate the patient as a patient is being taken to the CT scanner. After the CT scan is complete and the results are analyzed, eligible patients can receive Activase treatment on the CT table and the patient can remain in the scanner for a CT angiogram. If the patient is found to have a large vessel occlusion, the patient can go on to receive a mechanical thrombectomy, either at the same hospital or to be transported to another for surgery. Otherwise, the patient is sent to the ICU.

Amir Hassan: 18:55

Let's take a closer look at this example of a stroke treatment pathway and consider ways to reach specific target door-to-needle times. Hospital prenotification by EMS means the stroke and ED teams can be waiting for the patient. Bypassing the ED, the patient can be taken in the ambulance stretcher to the CT scanner to save time. A neurological exam, a patient history, vitals, and lab orders can be performed while the patient is being transported to the imaging suite. The CT scan should be started within 20 to 25 minutes of arrival, depending on if your door-to-needle goal is 45 or 60 minutes. Once the CT scan has been completed, the CT scan should be interpreted within 35 to 45 minutes of arrival. Eligible patients can begin their intravenous infusion of Activase on the CT table within 45 to 60 minutes. Patients who are suspected to have a large vessel occlusion can concurrently receive a CTA scan. There should be little or no delay between scans. Eligibility for mechanical thrombectomy can then be determined based on the CTA scan results.

Amir Hassan: 19:55

So to summarize this presentation, EMS protocols are an essential component of quality acute ischemic stroke patient care. Each treatment decision should take into account the capacity for the patient's deficits to be disabling and the patient's eligibility for Activase. Activase is indicated for the treatment of acute ischemic stroke. You need to exclude intracranial hemorrhage as the primary cause of stroke signs and symptoms prior to the initiation of treatment. You should initiate treatment as soon as possible, but within 3 hours after symptom onset. The most frequent adverse reaction associated with Activase acute ischemic stroke therapy is bleeding. Parallel processes can improve the speed and efficiency of acute ischemic stroke patient treatment and may improve patient outcomes. I hope this presentation has been informative. Thank you for watching.