Combo Thrombolytic Approach Fails to Reduce ICH in Stroke

A study evaluating a new approach using a combination of two thrombolytics designed to reduce bleeding risk in patients with acute ischemic stroke has not shown any benefit on the primary outcome of all intracranial hemorrhage (ICH).

However, there were some encouraging findings including a trend towards a reduction in symptomatic ICH, researchers report, and the combination approach did not show any depletion of fibrinogen levels, which suggests a potential lower bleeding risk.

"Although the main results of this study are neutral, we are encouraged that the combination approach with a low dose of alteplase followed by the new mutant pro-urokinase product looked as effective as full dose alteplase alone, and there were some promising signs signaling a potential lower bleeding risk," senior investigator, Diederik Dippel, MD, Erasmus University Medical Center, Rotterdam, Netherlands, told theheart.org | Medscape Cardiology.  

The DUMAS study (DUal thrombolytic therapy with Mutant pro-urokinase and low dose Alteplase for ischemic Stroke) was presented at the World Stroke Congress in Singapore on Oct. 28, by study co-author Nadinda van der Ende, MD, also from Erasmus University Medical Center. 

She pointed out that thrombolysis with intravenous alteplase increases the likelihood of a good outcome in acute ischemic stroke but can cause symptomatic intracranial hemorrhage, which can be associated with death and major disability.

Mutant pro-urokinase is a new thrombolytic agent, in development by Thrombolytic Science LLC, Cambridge, Massachusetts, formed by changing one amino acid in prourokinase to make it more stable. It is more fibrin specific than alteplase and therefore believed to have a lower risk of intracranial hemorrhage.

Fibrin is formed as the last step in the clotting process, and the precursor of fibrin in the blood is fibrinogen, van der Ende noted. Alteplase depletes fibrinogen, contributing to its increased bleeding risk, but mutant pro-urokinase is not believed to affect fibrinogen.

"Mutant pro-urokinase does not bind to intact fibrin. It only binds to fibrin that has already been primed by alteplase," she explained.

The hypothesis behind the current study is that giving a small dose of alteplase will break down fibrin in the clot enough to expose the binding sites for mutant pro-urokinase, which can then be given to continue to lyse the clot.  

As alteplase has a short half-life, it disappears quickly, and new fibrin is not affected. As mutant pro-urokinase can only lyse fibrin that is primed with alteplase, new hemostatic clots should stay intact. Animal studies have shown less bleeding from distant sites with this approach, van der Ende said.

The primary analysis of the phase 2 DUMAS study included 238 patients with mild ischemic stroke (median National Institutes of Health Stroke Scale [NIHSS] score 3) who met the standard criteria for IV alteplase.

They were randomized to alteplase alone at the regular dose of 0.9 mg/kg (max 90 mg) with a 10% bolus and the remaining given over 60 minutes; or to a combination of a 5 mg bolus of IV alteplase followed by mutant pro-urokinase at a dose of 40 mg given over 60 minutes.

The primary outcome was the rate of all intracranial hemorrhage (symptomatic and asymptomatic) detected by neuroimaging.  

This occurred in 14% of patients in the full-dose alteplase group vs 13% of patients in the combined alteplase/mutant pro-urokinase group, a non-significant difference: adjusted odds ratio 0.99 (95% CI, 0.46-2.14).

Secondary outcomes showed no significant differences in NIHSS scores at 24 hours or 5 to 7 days; functional outcome as measured by a shift analysis of the Modified Rankin Scale (mRS); final infarct volume; or perfusion deficit.

However, blood fibrinogen levels were not depleted and significantly higher in the alteplase/mutant pro-urokinase group than in the full dose alteplase alone group.

In terms of safety, symptomatic ICH occurred in three patients in the alteplase group (3%) and in none (0%) in the combined alteplase/mutant pro-urokinase group; death occurred in 4% vs 2% patients respectively; and major extracranial hemorrhage occurred in 1% in both groups.

Van der Ende concluded that the study showed an overall low rate of ICH; a combination of alteplase and mutant pro-urokinase was not superior to alteplase alone in reducing ICH rates in this population of patients with minor stroke; but mutant pro-urokinase appeared to be safe and, unlike alteplase, did not show any reduction in fibrinogen levels.

"We think the lack of an effect on fibrinogen with this new combination of a small alteplase bolus followed by mutant pro-urokinase infusion is promising," Dippel commented. "The fact that there was no symptomatic ICH with the combination treatment is also encouraging. Although the primary endpoint of this trial was neutral, we still believe this is a very interesting approach, with the potential for reduced bleeding compared with alteplase alone, but we need larger numbers to see an effect on outcomes."

Dippel also pointed out that the study only included patients with minor stroke who were not eligible for endovascular therapy and these patients have a low risk of a poor outcome and a low bleeding risk. 

They are hoping to do another study in patients with more severe stroke, who have a higher bleeding risk, and would have more to gain from this combination approach.

Because many patients with severe stroke now have immediate thrombectomy if they present to a comprehensive stroke center, a trial in severe stroke patients would have to be done in primary stroke centers, so if the patents are referred to thrombectomy, the thrombolytic would have a chance to work, Dippel added.

Commenting on the study for theheart.org | Medscape Cardiology, Stefan Kiechl, MD, Medical University of Innsbruck, Innsbruck, Austria, who is co-chair of the World Stroke Congress scientific committee, said, "Alteplase is not fibrin-specific, and also causes a degeneration of fibrinogen, which results in 'fibrinogen depletion coagulopathy.' It is assumed that 20%-40% of intracerebral bleeding after thrombolysis with alteplase is caused by this problem. DUMAS tests the combination of a substantially reduced alteplase (5 mg) dose plus mutant pro-urokinase to avoid this problem."

The new thrombolysis protocol, however, did not result in a lower bleeding risk, compared to the comparator alteplase," he added. "The main limitation of this study is that mainly patients with minor strokes were included. Patients with moderate and severe strokes, who have a substantial risk of bleeding, were not adequately addressed."

The DUMAS trial was funded by an unrestricted grant from Thrombolytic Science LLC, paid to the institution. Van der Ende and Dippel report no relevant disclosures.

14th World Stroke Conference. Presented Oct. 28, 2022.

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