NEW ORLEANS – The potential advantages of tenecteplase, a modified form of tissue plasminogen activator engineered to outperform the native molecule, finally shone through for treating patients with acute ischemic stroke.
A head-to-head comparison of tenecteplase against recombinant tissue plasminogen activator (TPA; alteplase) showed that the modified molecule produced better reperfusion and better clinical recovery 24 hours after treatment in a randomized trial of 75 Australian patients whose treatment was guided by CT brain imaging, Dr. Bill O’Brien reported at the International Stroke Conference.
Although Dr. O’Brien cautioned that this pilot study did not produce definitive results, the superiority of tenecteplase eclipsed its failure to surpass TPA in a randomized comparison of 112 patients reported in 2010.
The results "support using advanced imaging to identify the patients who are most likely to benefit" from tenecteplase, he said. The use of systematic CT brain imaging to select patients appeared to be the main factor that distinguished this study from the previous trial where tenecteplase failed to show an advantage, said Dr. O’Brien, a stroke physician at John Hunter Hospital in Newcastle, Australia.
Targeted patient selection may also explain why the tenecteplase treatment was so safe, resulting in a trend toward a reduced rate of type 2 parenchymal hemorrhages, compared with TPA, despite the superior thrombolytic activity shown by tenecteplase, he said.
Although the current trial had "compelling results," another study will follow to compare the two drugs by several 3-month outcomes, Dr. O’Brien said in an interview. The successful dosages of tenecteplase tested also have the advantage of being cheaper than the standard TPA dosage, he added.
Developed in the 1990s, tenecteplase resulted from three targeted amino acid substitutions in conventional TPA. This produced a molecule with increased fibrin specificity, and longer plasma half-life due to increased resistance to enzymatic degradation, which meant that it could be administered by an intravenous bolus instead of requiring continuous infusion like TPA. When used to treat myocardial infarctions, tenecteplase has also resulted in fewer bleeding complications than TPA.
The study enrolled 75 patients within 6 hours of onset of an ischemic stroke at any of three Australian hospitals, following selection by CT imaging to identify patients with a small infarct core and a large penumbra of salvageable brain. Researchers randomized patients to receive 0.1 mg/kg tenecteplase or 0.25 mg/kg tenecteplase by an intravenous bolus injection, or standard infusion with 0.9 mg/kg TPA. The patients averaged 70 years old, their average NIHSS (National Institutes of Health Stroke Scale) score at entry was about 14, and patients received treatment an average of about 3 hours after symptom onset.
The reperfusion rate after 24 hours was 78% among all 50 patients treated with tenecteplase, and 55% among the TPA treated patients, a statistically significant difference for one of the study’s two primary end points, Dr. O’Brien said. The second primary end point, change in NIHSS score after 24 hours, improved by an average of 8 points in all 50 tenecteplase patients, and by an average of 3 points in the TPA patients, also a significant difference.
The results appeared to show a dose-response relationship for tenecteplase, with the 25 patients who received the 0.25-mg/kg dosage having better reperfusion rates and reductions in their NIHSS scores than the 25 patients who received a 0.1-mg/kg dosage as well as the patients treated with TPA, but Dr. O’Brien did not report specific numbers from this analysis.
Of the 50 tenecteplase patients, 2 (4%) developed a type 2 parenchymal hemorrhage within 24 hours, compared with 4 (16%) of the 25 TPA-treated patients, a difference that trended toward significance. The rates of symptomatic intracerebral hemorrhages and death at 24 hours were similar with both drugs. But at 90 days after treatment, the combined rate of death or severe disability was 10% in the 50 tenecteplase patients and 25% in the TPA patients, a difference that also trended toward significance.
These findings contrast with a 2010 report from a randomized trial that compared three different tenecteplase dosages with TPA in a multicenter U.S. study of 112 patients (Stroke 2010;41:707-11). The results showed no significant differences between any of the tenecteplase dosages and TPA for any of the outcomes measured out to 90 days after treatment.
The major difference between the U.S. study and the new Australian study was in patient selection, Dr. O’Brien said. "We used imaging to balance the groups," and to select patients who stood to benefit most from effective reperfusion, he said.
Dr. O’Brien said that he and his associates had no disclosures.