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Thrombolytic Agent Recombinant Human Prourokinase Noninferior to Alteplase in Stroke Treatment
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Intravenous thrombolysis with recombinant human prourokinase resulted in a 16.4% lowered risk of systemic bleeding in comparison with alteplase treatment, which was consistent with previous phase 2 data.
Haiqing Song, MD, PhD
A recently published, randomized, open-label, phase 3 trial (NCT03541668) found that use of recombinant human prourokinase (rhPro-UK) within 4.5 hours of symptom onset in patients with acute ischemic stroke (AIS) was noninferior in terms of efficacy to traditionally used alteplase. The rhPro-UK group showed a similar rate of symptomatic intracranial hemorrhage (ICH) but fewer cases of systemic bleeding than the alteplase group.
The modified intention-to-treat population (mITT) included 663 patients, aged 18 to 80 years old, who were randomly assigned to 1:1 to either intravenous rhPro-UK (n = 330) or alteplase (n = 333). Led by Haiqing Song, MD, PhD, chief of the Department of Neurology at Capital Medical University in China, the study use a between-group difference of less than 10% to determine noninferiority, with scores of 0-1 on the modified Rankin Scale at 90 days as the primary outcome.
Conducted between May 2018 and May 2020, the median baseline National Institutes of Health Stroke Scale score was 6.00 (IQR, 5.00-9.00) for the cohort. Patients in the rhPro-UK group received doses of 35 mg intravenously with a bolus of 15 mg within 3 minutes and the remainder by continuous infusion within 30 minutes. Among the mITT, there were 23 deaths, and 619 (93.4%) completed the 3-month follow-up.
At 90 days, 65.2% (n = 215) an 64.3% (n = 214) of patients in the rhPro-UK and alteplase groups, respectively, achieved the primary outcome of an mRS score of 0 to 1 (risk difference [RD], 0.89; 95.4% CI, –6.52 to 8.29; P = .81), demonstrating noninferiority. Major neurological improvement at 24 hours was observed in 40.0% (n = 132) of the rhPro-UK group and 42.6% (n = 142) of the alteplase group (RD, –2.64; 95% CI, –10.14 to 4.85; P = .49). A Barthel Index score of 75 to 100 was obtained in 272 patients (82.4%) in the rhPro-UK group and 271 patients (81.4%) in the alteplase group (RD, 1.04; 95% CI, –4.82 to 6.90; P = .73).
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In terms of safety, death within 90 days was reported in 14 patients (4.2%) in the rhPro-UK group and 9 patients (2.7%) in the alteplase group (P = .30); however, each group had the same amount of deaths attributed to thrombolysis (1.5% each; P >.99). The 13 remaining deaths were considered unrelated to thrombolysis. In the rhPro-UK group, 5 deaths were attributed to the study drug, of which 4 deaths were caused by fatal symptomatic ICH and 1 death had an unknown cause, as was the case in the alteplase group.
Between the 2 groups, systemic bleeding within 90 days occurred in 42.2% of patients in the alteplase group vs 25.8% of those in the rhPro-UK group, a difference of 16.4% percentage points (P <.001). Both groups reported similar rates of serious systemic bleeding (rhPro-UK: 2.4%; alteplase: 2.7%; P >.99). Furthermore, the percentage of patients showing recurrent ischemic stroking in the rhPro-UK group was similar to that in the alteplase group (0.6% vs 0.6%; P >.99). There were no between-group differences in the incidence of any serious adverse event.
"Reduced risk of systemic bleeding in patients treated with rhPro-UK, indicating fewer complications, may mean lowered possibilities of use of blood products or hemostatic drugs, shorter hospital stays, and lower expenses," Song et al wrote. "In developing countries, patient adherence to alteplase may decrease in large amounts owing to potential hemorrhagic complications, a high cost, and lower availability. Unlike alteplase, rhPro-UK does not need to be administered according to body weight, making it easier to administer and saving time (30 minutes vs 1 hour). Moreover, rhPro-UK is more cost-effective in most cases and is easily available in all levels of hospitals in China. These factors suggest that rhPro-UK may be a better option than alteplase for the management of AIS in developing countries."
