Recombinant Human Prourokinase Noninferior to Alteplase in Acute Ischemic Stroke

Intravenous recombinant human prourokinase (rhPro-UK) demonstrated noninferiority to alteplase for patients with acute ischemic stroke (AIS) when administered within 4.5 hours of stroke onset, according to study findings published in JAMA Network Open.

Thrombolytic agent rhPro-UK has shown efficacy in treating acute myocardial infarction and has potential in effectively treating AIS in a phase 2 randomized clinical trial. The next step in the drug-approval process requires comparison of rhPro-UK with a thrombolytic agent that is currently approved for AIS in a phase 3 randomized controlled trial.

Researchers in China conducted this randomized, alteplase-controlled, open-label, phase 3, clinical trial (PROST; ClinicalTrials.gov Identifier: NCT03541668) from May 2018 to May 2020 across 35 medical centers in China. They analyzed the data between June and October of 2020.

Out of 684 patients who were screened, the researchers enrolled 674 eligible patients between the ages of 18 and 80 years with a diagnosis of AIS in their study. Of the 674 eligible patients, the researchers randomly assigned 663 (24.3% women; mean age, 61 years) into 2 treatment groups — 330 into the rhPro-UK group and 333 into the alteplase group.

Both treatments were administered intravenously within 4.5 hours of onset of stroke symptoms. Patients in the rhPro-UK group received 35 mg of the drug with a 15 mg bolus within 3 minutes, while patients in the alteplase group received 0.9 mg per kg body weight at a maximum of 90 mg with 10% administered intravenously as a bolus followed by 90% infusion within 1 hour.

The average baseline score per the National Institutes of Health Stroke Scale (NIHSS) totaled 6.00, ranging from 5 to 9. A total of 23 patients died before the end of the study, while 619 patients (93.4%) of the remaining patients finished the 3-month follow-up.

The primary outcome of interest was an excellent functional outcome based on a modified Rankin Scale (mRS) score between 0 and 1 after 90 days. Secondary outcomes included the following:

• major neurologic improvements indicated by reduction in NIHSS scores of 4 or greater or a score between 0 and 1 within 24 hours after treatment administration
• a Barthel Index score between 75 and 100 after 90 days post-treatment
• functional independence indicated by a mRS score between 0 and 2 after 90 days post-treatment

The researchers also evaluated safety outcomes, including all-cause mortality between 7 and 90 days after treatment, incidence of systemic bleeding within 90 days of treatment, incidence of symptomatic intracranial hemorrhage (ICH) within 90 days, and recurrence of ischemic stroke within 7 days of treatment.

After 3 months, 215 patients (65.2%) in the rhPro-UK and 214 patients (64.3%) in the alteplase group achieved excellent functional outcomes per the mRS (risk difference [RD], 0.89; 95.4% CI, -6.52 to 8.29; P =.81). There was a 16.4% lower risk for systematic bleeding with intravenous thrombolysis with rhPro-UK compared with alteplase treatment.

Within 24 hours of treatment administration, 132 patients (40.0%) in the rhPro-UK group and 142 patients (42.6%) in the alteplase group demonstrated major neurologic improvement (RD, -2.64; 95% CI, -10.14 to 4.85; P =.49).

After 90 days, 251 patients (76.1%) in the rhPro-UK group and 250 patients (75.1%) in the alteplase group reached a mRS score between 0 and 2 (RD, 0.99; 95% CI, -5.56 to 7.53; P =.77). Similarly, after 90 days, 272 patients (82.4%) in the rhPro-UK group and 271 patients (81.4%) in the alteplase group scored between 75 and 100 on the Barthel Index (RD, 1.04; 95% CI, -4.82 to 6.90; P =.73).

Death within 90 days occurred in 14 patients (4.2%) in the rhPro-UK group and 9 patients (2.7%) in the alteplase group (P =.30). Both groups demonstrated 5 deaths related to thrombolysis (1.5% in each group), whereas the remaining 13 deaths weren’t related to thrombolysis.

Recurrent ischemic stroke occurred at similar rates in the 2 treatment groups — 2 patients (0.6%) in each group. Additionally, symptomatic ICH occurred at similar rates between the 2 treatment groups, according to the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST; P >.99), the European Cooperative Acute Stroke Study (ECASS III; P >.99), and the National Institute of Neurological Disorders and Stroke (NINDS; P =.49).

In contrast, systemic bleeding within 90 days occurred with a significantly higher incidence in the alteplase group compared to the rhPro-UK group (42.2% vs 25.8%; P <.001); however, serious systemic bleeding occurred at similar rates across the 2 groups (2.4% in the rhPro-UK group vs 2.7% in the alteplase group).

The researchers noted that “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.”

Study limitations included missing data, use of a 10% noninferiority margin that is larger than the minimally clinically important difference suggested by consensus groups in 2005 and 2012, potential biases due to the open-label trial design. There was also a lack of mandated advanced imaging to ascertain perfusion lesion or vessel occlusion although use of CT scans perhaps made results more generalizable since this imaging is more widely available in smaller cities.

This article originally appeared on Neurology Advisor