Introduction
Our healthcare system continues to face significant obstacles related to acute ischemic stroke. Approximately seven lakh people have a new or recurrent stroke every year in the United States alone. Current projections indicate that number will increase to 3.4 million adults in the next ten years. A stroke is caused by an ischemic event in about 85 percent of cases, and a large percentage of stroke survivors need help with daily tasks.
Despite these dismal statistics, there have been a number of significant developments over the past 20 years that have revolutionized how to approach the diagnosis and care of patients with acute ischemic stroke. With the widespread use of intravenous Alteplase and, more recently, endovascular therapy, functional outcomes have significantly improved with appreciable declines in disability rates. The emphasis now is on prolonging these therapies beyond the previously established time windows.
What Are the Acute Reperfusion Treatments?
Acute ischemic stroke happens when a cerebral artery suddenly becomes blocked, depriving the downstream of brain tissue oxygen. Depending on how long the obstruction lasts, it may cause a permanent loss of neurological function carried out by the affected area of the brain. According to preclinical studies, 1.9 million neurons could lose their cells after each minute of ischemia. If the obstruction is removed before serious tissue damage takes place, reperfusion tissue may be able to repair such neuronal damage.
This key idea in acute reperfusion therapies for acute ischemic stroke is the distinction between the infarct core (a part of the brain that has irreparable damage) and the ischemic penumbra (a critically hypoperfused region of the brain that may be salvageable but is heading toward total infarction in the absence of prompt reperfusion). The reperfusion treatments are as follows-
Intravenous Thrombolysis:
Acute ischemic stroke patients have relied largely on intravenous thrombolysis for reperfusion therapy since the 1990s. There have been some significant advancements in these therapies that have enabled patients to receive these therapies for longer periods of time. A new generation of thrombolytic agents, like Tenecteplase, promises to provide better outcomes as well as lower drug administration costs.
Alteplase:
Since its initial approval following the historic NINDS (National Institute of Neurological Disorders and Stroke) trial, published in 1995, Alteplase or recombinant tissue plasminogen activator has been the first line of treatment for reperfusion in patients with acute ischemic stroke. By inducing a fibrinolytic cascade and by changing plasminogen into plasmin, Alteplase has an affinity for the fibrin component of blood clots and causes the dissolution of fibrin. Regardless of the NIHSS (National Institute of Health Stroke Scale) score, intravenous Alteplase has been shown to be beneficial for patients with disabling strokes. However, it is not strongly advised for patients who have had non-disabling strokes.
Tenecteplase:
Tenecteplase is a genetically altered form of Alteplase that has improved fibrin specificity, increased resistance to tissue plasminogen activator inhibitor, and a longer plasma half-life than Alteplase, allowing for a single dose intravenous bolus administration. After it showed comparable efficacy and lowered bleeding risks than Alteplase in a trial of patients with elevated ST-segment myocardial infarction, there has been a lot of interest in its use for the treatment of acute ischemic stroke in recent years.
Numerous studies have shown that patients who experience an acute ischemic stroke caused by a proximal intracranial large vessel occlusion benefit significantly less from IV (intravenous) Alteplase. Plasminogen levels are lower near the center of these large blood clots, which have been suggested as an explanation for this finding, providing less surface area for medications like Alteplase to conclude their enzymatic function and resulting in poor recanalization rates. Several observational studies showed that less than 20 percent of proximal LVOs (large vessel occlusion) treated with Alteplase experienced successful recanalization, which was associated with average clinical outcomes.
Combined Intravenous and Endovascular Therapy:
The goal of combining intravenous and endovascular approaches, also known as bridge therapy or multimodal reperfusion therapy (MMRT), is to benefit from the best of both techniques. This is done by allowing fast and early IV-tPA (intravenous tissue-type plasminogen activator) access within the first 4.5 hours after the onset of the stroke, and superior recanalization rates also for delayed time windows using endovascular therapy are both important. Notably, the Interventional Management of Stroke (IMS) I and II trials examined the viability and safety of a combination of interventions that included a low dose of 0.6 mg per kg IV-rtPA (intravenous tissue-type recombinant plasminogen activator) followed by an intra arterial rtPA within three hours of the stroke's onset to recanalize AIS (acute ischemic stroke). Bridge IV (intravenous) and IA (intra-arterial) therapy produced comparable proportions of ICH, mortality rates, and mRS at 90 days, making it comparable to IV-rtPA alone. Bridge therapy offered no additional benefits over IV-rtPA alone, according to the IMS III trial that came after.
What Is the Evolution of Reperfusion Therapy?
Thrombolysis, also referred to as clot busting, is a pharmaceutical procedure that involves the infusion of tPA analogs (tissue plasminogen activator), which causes the offending blood clot to break down. Blood clots are broken up by thrombolytic medications activating the proteolytic enzyme plasminogen to plasmin. Blood clots are made of fibrin molecules, and plasmin breaks the cross-links that good the fibrin molecules together. After that, the clot dissolves and is further broken down by other enzymes through a process called proteolysis, which eventually allows blood flow to resume. Thrombolytic medications are also known as plasminogen activators or fibrinolytic drugs due to their mode of action. Streptokinase, tPA (tissue plasminogen activator), and urokinase are the three main classes of plasminogen activators.
What Are the Limitations of Reperfusion Therapy?
Despite the significant benefits of mechanical thrombectomy (MT), only a small percentage of AIS patients (five to ten percent) receive it. Currently, vascular imaging tests like CTA (computed tomography angiography) or MRA (magnetic resonance angiography) are not frequently carried out when a patient presents. Based on the vascular imaging assessment of the ischemic penumbra, time since the onset of stroke symptoms, other baseline clinical factors, and prior history, the treating physician must make a quick decision. Only a few carefully chosen AIS patients would be suitable for MT, given the need for advanced imaging, particularly CTA.
Conclusion
The time window for mechanical thrombectomy may extend to 24 hours since the onset of symptoms in light of recent studies supporting the image-based selection of AIS patients for reperfusion therapy. However, additional research that examines bridge therapy or MMRT, in addition to sophisticated image-based approaches to choosing appropriate patients, may also broaden the time window for patient selection and would make a significant contribution to early thrombolytic strategies, better recanalization and improved clinical outcomes.
