Pro-urokinase a Less Expensive Thrombolytic for Stroke

ABU DHABI, UAE — Thrombolytic treatment with recombinant human pro-urokinase was non-inferior to alteplase in achieving an excellent functional outcome in acute ischemic stroke but showed a significantly lower rate of intracerebral hemorrhage, new phase 3 trial results showed.

This finding supports the use of recombinant human pro-urokinase as a potential alternative to alteplase for patients with acute ischemic stroke,” said lead investigator Shuya Li, MD, Beijing Tiantan Hospital, Beijing, China.

Li presented the trial on October 26 at the 16th World Stroke Congress (WSC) 2024.

A Landmark Trial

Carlos Molina, MD, Hospital Universitario Vall d’Hebron, Barcelona, Spain, who chaired the session where the study was presented, described it as a “landmark trial.”

Li explained that demand for thrombolysis for stroke treatment is growing, but there is currently a global shortage of these agents.

Recombinant human pro-urokinase could represent a new thrombolytic option, particularly for low-income countries, as it is much less expensive than alteplase or tenecteplase, she noted.

Another Chinese trial presented at the WSC meeting investigated the use of the same IV pro-urokinase product in mild ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score ≤ 5) but showed no benefit vs standard of care (no thrombolysis), a result consistent with several other trials of thrombolysis in mild stroke.

In her presentation on moderate or severe stroke (NIHSS score of 4-25), Li noted that a previous exploratory trial showed similar rate of favorable outcomes with recombinant human pro-urokinase and alteplase but a reduced risk for systemic bleeding with the pro-urokinase product.

The current trial aimed to establish the non-inferiority of recombinant pro-urokinase to alteplase for patients with acute ischemic stroke who were eligible for standard intravenous thrombolysis in a larger population.

The study had a prospective randomized, open, blinded endpoint design. It included 1552 patients with acute ischemic stroke within 4.5 hours of symptoms onset (median NIHSS score of 7) who were randomly assigned to intravenous recombinant pro-urokinase (15-mg bolus + 20-mg infusion over 30 minutes) or intravenous alteplase (standard use).

The primary efficacy outcome was the proportion of patients with an excellent functional outcome (modified Rankin Scale [mRS] score of 0-1) at 90 days, with a non-inferiority margin of 0.93 for the risk ratio.

The primary outcome occurred in 72.0% of the pro-urokinase group vs 68.6% of the alteplase group. Both the primary and the important secondary efficacy outcomes achieved the prespecified non-inferiority criteria.

The primary safety outcome was symptomatic intracerebral hemorrhage (sICH) as defined by SITS-MOST. This was observed in 0.3% in the pro-urokinase group and 1.3% in the alteplase group within 36 hours from symptom onset, a statistically significant difference (P = .02). This finding prompted applause from the audience when it was presented.

Other measures of bleeding were also reduced in the pro-urokinase group. These included major hemorrhage at 7 days (0.5% pro-urokinase vs 2.1% alteplase; P = .01); and clinically relevant nonmajor hemorrhage at 7 days (26.1% pro-urokinase vs 30.7% alteplase; P

Mortality at 7 days was 0.6% in the pro-urokinase group and 1.7% in the alteplase group (P = .06).

Li noted that the trial’s limitations included the fact that it was conducted in Chinese patients, and it is not known whether the findings would apply to other populations. In addition, she said, women were underrepresented, and patients who were eligible for endovascular thrombectomy were excluded.

‘An Interesting Option’

Commenting for Medscape Medical News, Michael Hill, MD, University of Calgary, Calgary, Alberta, Canada, said the study suggested IV pro-urokinase could be “an interesting option.”

However, he was cautious about the apparent substantial reduction in intracranial hemorrhage rate compared with alteplase.

“The ICH rate with pro-urokinase was so low I’m not sure that is plausible; there was probably some luck involved,” Hill said. “But it came out that the pro-urokinase is about half the cost of alteplase. Thus, it may be a realistic option for low- and middle-income countries where cost to the patient is a highly relevant factor in who is treated with thrombolytic agents,” he added.

Noting that pro-urokinase is not currently available in North America, and tenecteplase is now becoming the thrombolytic of choice in many countries because of its easier bolus administration, Hill said he could not see that changing based on these data.

No Benefit in Mild Stroke

The trial of pro-urokinase vs standard of care in patients with mild stroke (PUMICE) was presented by Carol Yunyun Xiong, MD, Beijing Tiantan Hospital.

For the study, 1446 patients who had an acute mild ischemic stroke with a baseline NIHSS score ≤ 5 within 4.5 hours of symptom onset received thrombolysis with intravenous pro-urokinase (total dose, 35 mg; 15 mg IV bolus followed by a 20-mg infusion over 30 minutes) or standard medical treatment (no thrombolysis).

The median NHSS score pre-randomization was 3 in the pro-urokinase group and 2 in the control group.

Results showed no difference in the primary outcome — an excellent functional outcome, defined as an mRS score 0-1 at 90 days. This was achieved by 88.5% of the pro-urokinase group vs 91% of the controls — a risk ratio of 0.97 (95% CI, 0.94-1.01; P = .12).

However, there was a suggestion of better early neurologic improvement at 25 hours (a secondary outcome) in the pro-urokinase group — 55.7% vs 44.3% (P

The key safety outcome — sICH occurred in 0.7% of pro-urokinase patients and 0% of controls. Moderate to severe bleeding occurred in 0.8% pro-urokinase vs 0.1% controls.

Xiong concluded that pro-urokinase is not superior to the standard of care for patients with mild ischemic stroke, a result that is consistent with several previous trials with other thrombolytics (alteplase or tenecteplase) in mild stroke, including PRISMS, ARAMIS, and TEMPO-2.

Hill said this trial provided confirmation that thrombolysis was not appropriate for patients with mild stroke.

“I think this seals it for minor stroke (NIHSS score of 0-5). We should not be thrombolysing these patients as a general rule,” he said.

The trial of pro-urokinase vs alteplase was funded by Tasly Biopharmaceuticals, China. The PUMICE trial was funded by the Beijing Science Fund for Young Scholars, with pro-urokinase provided by Tasly Biopharmaceuticals. The presenters reported no disclosures. Hill has been involved in clinical trials of tenecteplase.