Intravenous tenecteplase prior to endovascular treatment did not improve 90-day functional independence compared with endovascular treatment alone among patients with acute ischemic stroke due to proximal middle cerebral artery occlusion who presented 4.5 to 24 hours after last known well, according to findings from the phase 3 TNK-PLUS randomized clinical trial published in JAMA.
The multicenter, randomized, open-label, blinded end point superiority trial enrolled 391 adults at 40 centers in China. Patients had middle cerebral artery M1 or proximal M2 occlusion, a prestroke modified Rankin Scale score of 0 to 2, a National Institutes of Health Stroke Scale score of 6 to 25, and salvageable brain tissue on computed tomography perfusion or magnetic resonance perfusion-diffusion imaging. Imaging criteria included an ischemic core volume less than 70 mL, a mismatch ratio of at least 1.8, and a mismatch volume of at least 15 mL.
Patients were randomly assigned to receive intravenous tenecteplase at 0.25 mg/kg, up to 25 mg, prior to endovascular treatment (n = 199) or endovascular treatment alone (n = 192). The primary endpoint was functional independence at 90 days, defined as a modified Rankin Scale score of 0 to 2.
Functional independence occurred in 44% of patients who received tenecteplase prior to endovascular treatment and 43% of those who underwent endovascular treatment alone. The adjusted relative rate was 1.01, with a 95% confidence interval of 0.83 to 1.24, and the risk difference was 1%, with a 95% confidence interval compatible with approximately 9 percentage points of absolute harm to 11 percentage points of absolute benefit. The wide interval means the trial did not rule out a clinically meaningful effect in either direction.
Baseline characteristics were similar between groups. Median age was 68 years, 40% of patients were female, and median National Institutes of Health Stroke Scale score at admission was 13. Median time from symptom onset to randomization was approximately 10 hours. Among patients receiving tenecteplase, median time from hospital admission to tenecteplase administration was 90 minutes, and median time from tenecteplase administration to arterial puncture was 26 minutes.
The timing may be clinically important. In the discussion, the researchers noted that pre-endovascular treatment reperfusion rates have varied across trials in relation to tenecteplase dwell time: 6% in BRIDGE-TNK with a 16-minute dwell time, 10% in TNK-PLUS with a 26-minute dwell time, and 22% in EXTEND-IA TNK with a 43-minute dwell time. The 90-minute door-to-needle time in TNK-PLUS, attributed in part to additional imaging, consent, and randomization procedures, may have limited the amount of time tenecteplase had to act before arterial puncture.
Exploratory secondary outcomes also did not suggest a functional advantage with tenecteplase prior to endovascular treatment. No disability, defined as a modified Rankin Scale score of 0 to 1, occurred in 30% of patients in the tenecteplase group and 29% in the endovascular treatment–alone group. Modified Rankin Scale score 0 to 3 occurred in 63% and 62%, respectively. These secondary and other outcomes should be interpreted as exploratory because the trial did not adjust for multiple comparisons.
Reperfusion prior to endovascular treatment occurred in 10% of patients receiving tenecteplase and 7% of those assigned to endovascular treatment alone. However, the numerically higher preprocedural reperfusion rate did not translate into better functional outcomes. At 24 hours, reperfusion occurred in 45% and 46%, respectively, and complete recanalization occurred in 53% and 50%. The required 24-hour perfusion imaging was not completed in 104 patients because of clinical status.
Symptomatic intracranial hemorrhage within 36 hours occurred in 5% of patients in the tenecteplase group and 3% in the endovascular treatment–alone group. Although the difference was not statistically significant, the adjusted relative rate was 1.93, with a 95% confidence interval of 0.68 to 5.51, suggesting the safety data remain inconclusive due to limited event numbers. Death within 90 days occurred in 13% and 14%, respectively. The researchers also noted that the trial was likely not powered to detect safety differences.
Prespecified subgroup analyses did not show treatment-effect heterogeneity by age, sex, baseline stroke severity, occlusion site, Alberta Stroke Program Early Computed Tomography Score, core volume, timing metrics, collateral grade, or cause of stroke. Although the point estimate favored tenecteplase among patients with longer time from randomization to revascularization, neither the subgroup effect nor the interaction test was statistically significant.
Intracranial atherosclerosis accounted for 65% of stroke etiology in TNK-PLUS, a distribution that may differ from many Western stroke populations. Because thrombolytics may be less effective in plaque-related occlusions than in fibrin-rich embolic clots, this etiologic profile could affect the applicability of the findings, although the trial did not show a treatment interaction by stroke cause.
The findings also apply specifically to patients presenting directly to centers with endovascular treatment capability. The researchers emphasized that the results should not be extrapolated to patients presenting to hospitals without onsite endovascular treatment, including those requiring interfacility transfer. In those settings, longer expected delays before arterial puncture may allow more thrombolytic dwell time, and bridging tenecteplase may remain a clinically relevant question.
The trial included a prespecified promising-zone adaptive sample size reestimation. At interim analysis, conditional power was 0.03, below the prespecified promising zone of 0.33 to 0.80, so the sample size was not increased and the final enrollment remained near the minimum planned sample size. This means the trial’s own interim data suggested it was highly unlikely to detect a statistically significant treatment effect even before final enrollment was completed.
“In this randomized trial of patients with ischemic stroke due to a proximal middle cerebral artery occlusion and who had salvageable tissue presenting directly to an EVT center within 4.5 to 24 hours, treatment with intravenous tenecteplase before EVT did not increase the likelihood of functional independence compared with EVT alone,” wrote lead study author Yunyun Xiong, MD, of Beijing Tiantan Hospital, Capital Medical University in China, and colleagues.
Disclosures: Co-study author Marc Fisher, MD, reported consulting relationships with Simcere USA, Lumosa, and Revalesio and participation on data and safety monitoring boards for Moleac and Takeda. Co-study author Thanh N. Nguyen, MD, reported serving as an associate editor for Stroke, speaking for Genentech, and consulting for Bayer, Medtronic, and Route 92. No additional disclosures were reported.
The study received support from the Natural Science Foundation of Beijing Municipality, the Beijing Municipal Science and Technology Commission, the Administrative Commission of Zhongguancun Science Park, the National Natural Science Foundation of China, and China Shijiazhuang Pharmaceutical Company Recomgen Pharmaceutical.
Source: JAMA
