In recent years, thrombolytic therapy, using medications to dissolve blood clots in blood vessels, has revolutionized the treatment of ischemic strokes. Among these clot-busting drugs, alteplase has become a cornerstone of acute ischemic stroke treatment. However, the quest for optimizing patient outcomes continues to drive researchers toward the exploration of potentially beneficial combinations of thrombolytic agents.
One such promising candidate is prourokinase, a precursor to the enzyme urokinase, which plays a critical role in clot dissolution. The combination of mutant prourokinase and alteplase in particular has attracted considerable attention from researchers and clinicians. Yet, despite its potential promise, the safety and efficacy of this combination remains underexplored.
In this context, the recent study “Safety and Efficacy of Dual Thrombolytic Therapy With Mutant Prourokinase and Small Bolus Alteplase for Ischemic Stroke”, conducted by van der Ende and colleagues, provides a valuable contribution to our understanding of these therapies. This article delves into the findings of this pioneering phase 2 clinical trial, elucidating its methodology, results, and potential implications for stroke treatment strategies.
Their findings shed light on the potential of dual thrombolytic treatment as an alternative for patients with minor ischemic stroke who are not eligible for endovascular therapy. As we navigate through this comprehensive study, we aim to provide valuable insights into the safety and efficacy of this innovative therapeutic combination in the landscape of stroke management.
The Treatments being Compared
- A combination of small bolus alteplase and mutant prourokinase
- Alteplase alone
Alteplase is a medication commonly used in ischemic strokes to dissolve the blood clots that are causing the stroke. Prourokinase is another thrombolytic agent, and in this study, a mutant form of it is being used alongside alteplase.
The study found that the rates of intracranial hemorrhage (bleeding within the skull, which is a potential serious side effect of thrombolytic therapy) were almost identical between the two groups (13.2% in the intervention group and 13.7% in the control group).
The treatment with mutant prourokinase showed a shift towards better outcomes on the modified Rankin Scale (a measure of disability or dependence in daily activities following stroke) at 30 days, but this shift was not statistically significant.
The conclusion drawn from these findings is that, for patients with minor ischemic stroke who were not eligible for endovascular therapy (a minimally invasive procedure often used to remove or break up blood clots), the dual thrombolytic treatment with small bolus alteplase and mutant prourokinase was not proven to be safer than treatment with alteplase alone. However, more studies are needed to confirm these findings and to determine whether the combination treatment might have other benefits not captured in this study.
Definitions
- Thrombolytic:
- Definition: These are drugs that dissolve blood clots that have formed in blood vessels, which can improve blood flow and prevent damage to tissues and organs.
- Etymology: The term is derived from the Greek words “thrombos,” meaning clot, and “lysis,” meaning to loosen or dissolve.
- Prourokinase:
- Definition: Prourokinase is the inactive precursor to urokinase, an enzyme that catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for clot breakdown.
- Etymology: The term combines “pro-“, a prefix meaning before, with “urokinase”, a term derived from “urinary” and “kinase.” “Urinary” refers to the fact that it was first isolated from human urine, and “kinase” is a type of enzyme that transfers phosphate groups from high-energy molecules to specific substrates, a process that is critical in energy transfer.
- Bolus:
- Definition: A bolus is a single, large dose of a drug usually given for an immediate effect or a rapid intervention.
- Etymology: The term originates from the Latin word “bolus,” which means a small ball. In medicine, it refers to a large amount of a substance given intravenously at once.
- Alteplase:
- Definition: Alteplase is a thrombolytic drug that works by stimulating the conversion of plasminogen to plasmin, which then breaks down blood clots. It’s typically used in the treatment of heart attacks and strokes caused by blood clots.
- Etymology: The name is an acronym derived from ‘Acetylated’ + ‘Liste’ (denoting lineage from the original strain of human tissue-type plasminogen activator used to create the drug) + ‘plasminogen’ + ‘activator’. The ‘alte-‘ prefix means ‘other’ or ‘alternative’.
Study Methodology and Participants
The study orchestrated by van der Ende and team was a phase 2 randomized clinical trial. This trial design allowed the researchers to control for potential confounding variables, increasing the likelihood that any observed differences in outcomes were due to the treatments under investigation.
The researchers sought to answer a critical question: Is dual thrombolytic treatment with small bolus alteplase and mutant prourokinase safer than treatment with alteplase alone in patients with ischemic stroke?
A total of 238 participants with ischemic stroke were included in the study. This sample size provided the statistical power to detect meaningful differences in outcomes between the intervention group (those receiving the dual treatment) and the control group (those receiving alteplase alone).
Primary Outcomes and Findings
In the primary analysis, the researchers assessed the safety of the dual treatment approach by measuring the occurrence of intracranial hemorrhage—a serious side effect associated with thrombolytic therapies—in both groups.
Intriguingly, the incidence of intracranial hemorrhage was almost identical between the intervention and control groups, with rates of 13.2% and 13.7% respectively. This finding suggests that the addition of mutant prourokinase to alteplase treatment does not significantly increase the risk of intracranial bleeding.
In terms of efficacy, the researchers evaluated the participants’ scores on the modified Rankin Scale—a tool used to measure the degree of disability or dependence in daily activities after a stroke—at 30 days post-treatment. The use of mutant prourokinase indicated a trend toward better outcomes on the scale, although the shift was not statistically significant.
Conclusion and Implications for Stroke Treatment
From the results obtained, it can be deduced that for patients with minor ischemic stroke who were not eligible for endovascular therapy, the dual thrombolytic treatment with small bolus alteplase and mutant prourokinase was not definitively proven to be safer than treatment with alteplase alone.
While this study offers valuable insights, more investigations are needed to fully explore the potential of dual thrombolytic therapies in ischemic stroke treatment. The researchers’ efforts underscore the commitment to optimizing stroke management and improving patient outcomes, and pave the way for future research in this crucial area of medicine.
Citation: van der Ende, N. A. M., Roozenbeek, B., Smagge, L. E. M., et al. (2023). Safety and Efficacy of Dual Thrombolytic Therapy With Mutant Prourokinase and Small Bolus Alteplase for Ischemic Stroke: A Randomized Clinical Trial. JAMA Neurol. Published online May 22, 2023. doi:10.1001/jamaneurol.2023.1262
Similar Studies
Various studies had been conducted to compare the safety and efficacy of different thrombolytic agents for ischemic stroke.
Studies have shown that the use of thrombolytic agents such as alteplase (also known as recombinant tissue plasminogen activator or rt-PA) can be beneficial in treating ischemic stroke. The NINDS rt-PA Stroke Study, for instance, demonstrated that patients treated with alteplase within 3 hours of stroke onset were at least 30% more likely to have minimal or no disability at 3 months, compared with those receiving a placebo1.
Meanwhile, other studies were investigating alternative thrombolytic agents and combinations thereof. A trial by the PRISMS investigators studied the use of prourokinase in acute ischemic stroke and found it to be beneficial, though it carried a risk of symptomatic intracranial hemorrhage2.
- National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. (1995). Tissue plasminogen activator for acute ischemic stroke. The New England Journal of Medicine, 333(24), 1581–1587.
- Furlan A, et al. (1999). Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA, 282(21), 2003-2011.
Glossary of terms:
- Alteplase: A thrombolytic drug that works by stimulating the conversion of plasminogen to plasmin, which then breaks down blood clots. It’s typically used in the treatment of heart attacks and strokes caused by blood clots.
- Bolus: A single, large dose of a drug usually given for an immediate effect or a rapid intervention.
- Control Group: A group of participants in a study who receive the standard treatment or a placebo, rather than the experimental treatment, and are used as a benchmark to compare the results of the intervention group.
- Endovascular Therapy: A minimally invasive procedure often used to remove or break up blood clots.
- Intracranial Hemorrhage: Bleeding within the skull, which is a potential serious side effect of thrombolytic therapy.
- Ischemic Stroke: A type of stroke that occurs when the flow of blood to the brain is blocked, usually by a blood clot.
- Modified Rankin Scale: A commonly used measure of disability or dependence in daily activities following stroke.
- Mutant Prourokinase: A modified version of prourokinase, which is the inactive precursor to urokinase, an enzyme that catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for clot breakdown.
- Phase 2 Clinical Trial: The second of four phases of clinical trials, during which the drug or treatment is given to a larger group of people to see if it is effective and to further evaluate its safety.
- Thrombolytic: Drugs that dissolve blood clots that have formed in blood vessels, which can improve blood flow and prevent damage to tissues and organs.