Glucose Control and Risk of Symptomatic Intracerebral Hemorrhage Following Thrombolysis for Acute Ischemic Stroke: A SHINE Trial Analysis.

BACKGROUND AND OBJECTIVES: Baseline hyperglycemia is associated with worse outcomes in acute ischemic stroke (AIS), including higher risk of symptomatic intracerebral hemorrhage (sICH) following treatment with thrombolysis. Prospective data are lacking to inform management of post-thrombolysis hyperglycemia. In a prespecified analysis from the Stroke Hyperglycemia Insulin Network Effort (SHINE) trial of hyperglycemic stroke management, we hypothesized that post-thrombolysis hyperglycemia is associated with a higher risk of sICH. METHODS: Hyperglycemic AIS patients <12 hours onset were randomized to intensive insulin (target range 80-130 mg/dL) vs standard sliding scale (80-179 mg/dL) over a 72-hour period, stratified by treatment with thrombolysis. Three board-certified vascular neurologists independently reviewed all sICH events occurring within 7 days, defined by neurologic deterioration of ≥4 points on the NIH Stroke Scale (NIHSS). Associations between blood glucose control and sICH were analyzed using logistic regression accounting for NIHSS, age, systolic blood pressure, onset to thrombolysis time, and endovascular therapy (odds ratios [OR], 95% CI). Additional analysis compared patients in a high-risk group (age older than 60 years and NIHSS ≥8) vs all others. Categorical variables and outcomes were compared using the χ2 test (p < 0.05). RESULTS: Of 1151 SHINE participants, 725 (63%) received thrombolysis (median age 65 years, 46% women, 29% Black, 18% Hispanic). The median NIHSS was 7, baseline blood glucose was 187 (interquartile range 153-247) mg/dL, and 80% were diabetic. Onset to thrombolysis time was 2.2 hours (1.6-2.9). Post-thrombolysis sICH occurred in 3.6% (3.0% intensive vs 4.3% standard glucose control, OR 1.10, 0.60-2.01, p = 0.697). In the first 12 hours, every 10 mg/dL higher glucose increased the odds of sICH (OR 1.08, 1.03-1.14, p = 0.004), and a greater proportion of glucose measures in the normal range (80-130 mg/dL) decreased the odds of sICH (0.89, 0.80-0.99, p = 0.030). These associations were strongest in the high-risk group (age older than 60 years and NIHSS ≥8). DISCUSSION: In this prespecified analysis from the SHINE trial, intensive insulin therapy was not associated with a reduced risk of post-thrombolysis sICH compared with standard sliding scale. However, early post-thrombolysis hyperglycemia was associated with a higher risk of sICH overall, particularly in older patients with more severe strokes. Further prospective research is warranted to address the risk of sICH in hyperglycemic stroke patients undergoing endovascular therapy. TRIAL REGISTRATION INFORMATION: NCT01369069.

Spurious Hyperphosphatemia in a Patient with Chronic Kidney Disease - a Rare Case of Alteplase Contamination.

Spurious hyperphosphatemia, a rare occurrence, typically arises from substances in a patient's blood interfering with the colorimetric method for serum phosphate measurement. We present a case of factitious hyperphosphatemia caused by alteplase-contaminated blood samples in an 88-year-old CKD patient on hemodialysis, leading to misleadingly high phosphorus levels. Thorough investigations ruled out other etiologies, highlighting the necessity of stringent adherence to blood collection protocols to prevent sample contamination and avert erroneous laboratory results. This unique cause of hyperphosphatemia should be considered in the differential diagnosis when encountering unexplained elevations in phosphorus levels, particularly in the context of normal blood calcium levels.

Comprehensive Review of Tenecteplase for Thrombolysis in Acute Ischemic Stroke.

Although intravenous thrombolysis with alteplase remains the primary treatment for acute ischemic stroke, tenecteplase has shown potential advantages over alteplase. Animal studies have demonstrated the favorable pharmacokinetics and pharmacodynamics of tenecteplase. Moreover, it is easier to administer. Clinical trials have demonstrated that tenecteplase is not inferior to alteplase and may even be superior in cases of acute ischemic stroke with large vessel occlusion. Current evidence supports the time and cost benefits of tenecteplase, suggesting that it could potentially replace alteplase as the main option for thrombolytic therapy, especially in patients with large vessel occlusion.

[Comparative characteristics of the efficacy and safety of the original alteplase and its complete biosimilar in the treatment of ischemic stroke in real clinical practice]. / Sravnitel'naya kharakteristika effektivnosti i bezopasnosti original'noi alteplazy i ee bioanaloga pri lechenii ishemicheskogo insul'ta v real'noi klinicheskoi praktike.

OBJECTIVE: To conduct a comparative analysis between the original alteplase and its biosimilar in terms of efficacy and safety in real clinical practice in the Republic of Belarus. MATERIAL AND METHODS: The cohort study included 420 patients. All included patients underwent thrombolytic therapy with alteplase within 4.5 hours of the onset of stroke symptoms according to the approved tactics of the Republic of Belarus and international recommendations. The patients were divided into 2 groups: 215 received the drug Revelisa, 205 - Actilyse. RESULTS: The patients were comparable in gender, age, ASPECTS assessment, but had statistically significant difference in NIHSS was found, due to the large number of patients with NIHSS=16-25 in the Actilyse group. The assessment of premorbid disability also showed a statistically significant difference: there were more patients in the Revelisa group who had functional limitations of varying degrees before the disease, 83 (38.6%) versus 62 (28.3%) patients in the comparison group. Clinical outcomes were comparable, the proportion of patients achieving mRS=0-1 at discharge was 41.5% in group A and 42.8% in group P. The Revelisa demonstrated a statistically significant lower number of deaths in 15 (7.0%) and 29 (14.1%) in the comparison group. The development of a greater number of clinically insignificant petechial hemorrhages was noted after the use of Actilyse. CONCLUSION: The analysis demonstrated a high level of safety in the use of alteplase preparations in routine practice. The compared fibrinolytics had comparable effectiveness in achieving functional independence after ischemic stroke, despite the more premorbid disability of patients who received a biosimilar.

Tenecteplase versus alteplase for acute ischemic stroke: a systematic review and meta-analysis of randomized and non-randomized studies.

OBJECTIVE: Alteplase is the current standard of care for acute ischemic stroke. Tenecteplase is a newer fibrinolytic agent with preferable administration and lower costs; however, its comparative effectiveness to alteplase remains uncertain. We set out to perform a systematic review and meta-analysis to establish the benefits and harms of tenecteplase versus alteplase for acute ischemic stroke. METHODS: We searched PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov from inception to April 2023 for randomized and non-randomized studies that compared tenecteplase versus alteplase for acute ischemic stroke. Paired reviewers independently assessed risk of bias and extracted data. We performed both conventional meta-analyses and Bayesian network meta-analyses (NMA) with random-effects models and used the GRADE approach to evaluate the certainty of evidence. Our primary efficacy outcome was excellent functional outcome at 3 months, defined as a score of 0-1 on the modified Rankin Scale. Our primary safety outcomes were symptomatic intracranial hemorrhage and all-cause mortality. RESULTS: Thirty-six studies were eligible for review, including 12 randomized (n = 5533) and 24 non-randomized studies (n = 44,956). Moderate certainty evidence showed that there was no difference between tenecteplase and alteplase in increasing the proportion of patients achieving excellent functional outcome at 3 months (odds ratio [OR], 1.10; 95% CI 0.98-1.23; risk difference [RD] 2.4%, 95% CI - 0.5 to 5.2), while moderate certainty evidence from NMA suggested that 0.25 mg/kg tenecteplase significantly improved excellent functional outcome at 3 months (OR, 1.16; 95% credible interval 1.02-1.32). Moderate certainty evidence showed that, compared to alteplase, tenecteplase may make little to no difference in the prevalence of symptomatic intracranial hemorrhage (OR, 1.12; 95% CI 0.79-1.59; RD 0.3%, 95% CI - 0.5 to 1.4), and probably reduces all-cause mortality (adjusted odds ratio [aOR], 0.44; 95% CI 0.30-0.64; RD - 4.6%; 95% CI - 5.8 to - 2.9). CONCLUSIONS: Moderate certainty evidence suggested that there was little to no difference between tenecteplase and alteplase in increasing the proportion of patients achieving excellent functional outcome at 3 months and the risk of symptomatic intracranial hemorrhage, while compared to alteplase, tenecteplase probably reduce all-cause mortality. Administration of 0.25 mg/kg tenecteplase after acute ischemic stroke is suggestive of increasing the proportion of patients that achieve excellent functional outcome at 3 months.

Association of Time to Thrombolysis With Early Reperfusion After Alteplase and Tenecteplase in Patients With Large Vessel Occlusion.

BACKGROUND AND OBJECTIVES: Early treatment with intravenous alteplase increases the probability of lytic-induced reperfusion in large vessel occlusion (LVO) patients. The relationship of tenecteplase-induced reperfusion and the timing of thrombolytic administration has not been explored. In this study, we performed a comparative analysis of tenecteplase and alteplase reperfusion rates and assessed their relationship to the time of thrombolytic administration. METHODS: Patients who were initially treated with a thrombolytic within 4.5 hours of symptom onset were pooled from the Royal Melbourne Stroke Registry, EXTEND-IA, EXTEND-IA TNK, and EXTEND-IA TNK part 2 trials. The primary outcome, thrombolytic-induced reperfusion, was defined as the absence of retrievable thrombus or >50% reperfusion at initial angiographic assessment (or repeat CT perfusion/angiography). We compared the treatment effect of tenecteplase and alteplase through fixed-effects Poisson regression modelling. RESULTS: Among 846 patients included in the primary analysis, early reperfusion was observed in 173 (20%) patients (tenecteplase: 98/470 [21%], onset-to-thrombolytic time: 132 minutes [interquartile range (IQR): 99-170], and thrombolytic-to-assessment time: 61 minutes [IQR: 39-96]; alteplase: 75/376 [19%], onset-to-thrombolytic time: 143 minutes [IQR: 105-180], thrombolytic-to-assessment time: 92 minutes [IQR: 63-144]). Earlier onset-to-thrombolytic administration times were associated with an increased probability of thrombolytic-induced reperfusion in patients treated with either tenecteplase (adjusted risk ratio [aRR] 1.05 per 15 minutes [95% confidence interval (CI) 1.00-1.12] or alteplase (aRR 1.06 per 15 minutes [95% CI 1.00-1.13]). Tenecteplase remained associated with higher rates of reperfusion vs alteplase after adjustment for onset-to-thrombolytic time, occlusion site, thrombolytic-to-assessment time, and study as a fixed effect, (adjusted incidence rate ratio: 1.41 [95% CI 1.02-1.93]). No significant treatment-by-time interaction was observed (p = 0.87). DISCUSSION: In patients with LVO presenting within 4.5 hours of symptom onset, earlier thrombolytic administration increased successful reperfusion rates. Compared with alteplase, tenecteplase was associated with a higher probability of lytic-induced reperfusion, independent of onset-to-lytic administration times. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifiers: NCT02388061, NCT03340493. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that among patients with LVO receiving a thrombolytic, reperfusion was more likely with tenecteplase than alteplase.

Tenecteplase versus alteplase for the treatment of acute ischemic stroke: a meta-analysis of randomized controlled trials.

OBJECTIVES: Tenecteplase, a modified variant of alteplase with greater fibrin specificity and longer plasma half-life, may have better efficacy and safety than alteplase in patients with acute ischemic stroke (AIS). We aimed to compare the benefits and risks of tenecteplase versus alteplase in the treatment of AIS. METHODS: Electronic databases were searched up to 10 February 2023 for randomized controlled trials evaluating the effect of tenecteplase versus alteplase in the treatment of AIS. The primary outcome was functional outcome at 90 days, and secondary outcomes including the symptomatic intracranial haemorrhage (SICH), and major neurological improvement. Subgroup analysis was performed based on the different dosage of tenecteplase. RESULTS: Ten studies with a total of 5123 patients were analysed in this meta-analysis. Overall, no significant difference between tenecteplase and alteplase was observed for functional outcome at 90 days (excellent: OR 1.08, 95%CI 0.93-1.26, I2 = 26%; good: OR 1.04, 95%CI 0.83-1.30, I2 = 56%; poor: OR 0.95, 95%CI 0.75-1.21, I2 = 31%), SICH (OR 1.12, 95%CI 0.79-1.59, I2 = 0%), and early major neurological improvement (OR 1.26, 95%CI 0.80-1.96, I2 = 65%). The subgroup analysis suggested that the 0.25 mg/kg dose of tenecteplase had potentially greater efficacy and lower symptomatic intracerebral haemorrhage risk compared with 0.25 mg/kg dose tenecteplase. CONCLUSIONS: Among AIS patients, there was no significant difference on clinical outcomes between tenecteplase and alteplase. Subgroup analysis demonstrated that 0.25 mg/kg doses of tenecteplase were more beneficial than 0.4 mg/kg doses of tenecteplase. Further studies are required to identify the optimal dosage of tenecteplase.

Randomized controlled trials exploring comparative efficacy and safety of tenecteplase and alteplase have been yielding inconsistent results on various outcomes and merit the conduction of a meta-analysis to adequately answer these questions.Analysis of evidence from randomized studies suggests that tenecteplase is as safe as alteplase for the treatment of acute ischemic stroke and tenecteplase is potentially associated with more favourable outcomes.Tenecteplase at 0.25 mg/kg dose is more efficacious and at least as safe as alteplase for stroke thrombolysis.

Predictive model for the risk of hemorrhagic transformation after rt-PA intravenous thrombolysis in patients with acute ischemic stroke: A systematic review and meta-analysis.

OBJECTIVE: To systematically review the risk prediction model of Hemorrhages Transformation (HT) after intravenous thrombolysis in patients with Acute Ischemic Stroke (AIS). METHODS: Web of Science, The Cochrane Library, PubMed, Embase, CINAHL, CNKI, CBM, WanFang, and VIP were searched from inception to February 25, 2023 for literature related to the risk prediction model for HT after thrombolysis in AIS. RESULTS: A total of 17 included studies contained 26 prediction models, and the AUC of all models at the time of modeling ranged from 0.662 to 0.9854, 16 models had AUC>0.8, indicating that the models had good predictive performance. However, most of the included studies were at risk of bias. the results of the Meta-analysis showed that atrial fibrillation (OR=2.72, 95% CI:1.98-3.73), NIHSS score (OR=1.09, 95% CI:1.07-1.11), glucose (OR=1.12, 95% CI:1.06-1.18), moderate to severe leukoaraiosis (OR=3.47, 95% CI:1.61-7.52), hyperdense middle cerebral artery sign (OR=2.35, 95% CI:1.10-4.98), large cerebral infarction (OR=7.57, 95% CI:2.09-27.43), and early signs of infarction (OR=4.80, 95% CI:1.74-13.25) were effective predictors of HT after intravenous thrombolysis in patients with AIS. CONCLUSIONS: The performance of the models for HT after thrombolysis in patients with AIS in the Chinese population is good, but there is some risk of bias. Future post-intravenous HT conversion prediction models for AIS patients in the Chinese population should focus on predictors such as atrial fibrillation, NIHSS score, glucose, moderate to severe leukoaraiosis, hyperdense middle cerebral artery sign, massive cerebral infarction, and early signs of infarction.

Hemorrhage induced by antithrombotic agents: new insights from a real-world pharmacovigilance study.

BACKGROUND: Hemorrhage represents the most common and serious side effect of antithrombotic agents. Many studies have compared the risk of bleeding between different antithrombotic agents, but analysis of time-to-onset for hemorrhage induced by these drugs is yet sparse. METHODS: We conducted a retrospective study based on the adverse drug reaction reports on antithrombotic agents collected by the Henan Adverse Drug Reaction Monitoring Center. We assessed the reporting odds ratio to determine the disproportionate reporting signals for bleeding and the Weibull shape parameter was used to evaluate the time-to-onset data. RESULTS: In the signal detection, crude low molecular weight heparin-hemorrhage was found as a positive signal. The hemorrhage for most antithrombotic agents was random failure profiles. In particular, the hazard of hemorrhage decreased over time for warfarin and clopidogrel and increased for alteplase, nadroparin, and dipyridamole. CONCLUSION: We found that the risk of bleeding in patients taking Crude low molecular weight heparins was significantly higher compared to other antithrombotic agents, but with a small magnificence, which may be attributed to the severely irrational use of this medication under improper management. Statistics in days, results showed that the risk of bleeding decreased over time for warfarin and clopidogrel and increased for alteplase, nadroparin, and dipyridamole.

Efficacy and safety outcomes of Tenecteplase versus Alteplase for thrombolysis of acute ischemic stroke: A meta-analysis of 9 randomized controlled trials.

BACKGROUND: In recent years, Tenecteplase (TNK), a genetically modified variant of alteplase, has been verified as a potential substitute for alteplase in the reperfusion therapy of acute ischemic stroke (AIS). Given the emergence of new randomized controlled trials (RCTs) of this subject, a meta-analysis was conducted to evaluate the present comparative evidence regarding the efficacy and safety outcomes of TNK and alteplase in thrombolysis for AIS. METHODS: Following predefined inclusion criteria, we searched the databases of PubMed, Web of Science, and Cochrane Library. RCTs satisfying our inclusion criteria were selected for meta-analysis. Outcome indicators were categorized into efficacy outcomes (early vessel recanalization, excellent recovery, good recovery and early neurological improvement) and safety outcomes (poor recovery, symptomatic intracerebral hemorrhage, parenchymal hemorrhage type 2(PH2) post thrombolysis, and mortality). We extracted data on efficacy outcomes and safety outcomes for patients with AIS in the TNK group at a dose of 0.25 mg/kg and the alteplase group at a dose of 0.9 mg/kg, and expressed the relative risks between the 2 groups as odds ratios (ORs) and 95% confidence intervals (CIs) using the Mantel-Haenszel method. For further insight, we performed a network meta-analysis using a Bayesian framework to compare different doses of TNK (0.1, 0.25, 0.32, and 0.4 mg/kg) with alteplase (0.9 mg/kg). RESULTS: A total of 2994 patients in 9 RCTs comparing efficacy and safety outcomes in patients with AIS treated with TNK and alteplase were included. In a pairwise analysis of TNK 0.25 mg/kg and alteplase 0.9 mg/kg, regarding efficacy outcomes, the aggregated results show that TNK 0.25 mg/kg statistically significant increased early vessel recanalization (N = 368, TNK vs. alteplase, OR: 2.07,95%CI: [1.19,3.59], I2 = 0%) and excellent recovery (N = 3548, TNK vs. alteplase, OR: 1.15,95%CI: [1.01,1.32], I2 = 0%). There was no significant difference in good recovery (N = 3486, TNK vs. alteplase, OR: 1.38,95%CI: [0.89,2.15], I2 = 84%) or early neurological improvement (N = 1686, TNK vs. alteplase, OR: 1.06,95%CI: [0.87,1.28], I2 = 24%) between the TNK 0.25 mg/kg group and the alteplase 0.9 mg/kg group. In the safety outcomes, pooled results showed no significant difference in poor recovery (N = 3548, TNK vs. alteplase, OR: 0.94,95%CI: [0.81,1.10], I2 = 0%) and symptomatic intracerebral hemorrhage (N = 3567, TNK vs. alteplase, OR: 1.06,95%CI: [0.70,1.60], I2 = 0%) and PH2(N = 3103, TNK vs. alteplase, OR: 1.26,95%CI:[0.39,4.07], I2 = 56%)and mortality (N = 3447, TNK vs. alteplase, OR: 0.99,95%CI: [0.80,1.23], I2 = 33%) between the TNK group and the alteplase group. In a network meta-analysis, competing treatments were not significantly different from one another (TNK 0.1 mg/kg, TNK 0.25 mg/kg, TNK 0.32 mg/kg, TNK 0.4 mg/kg, alteplase 0.9 mg/kg) in either efficacy outcomes or safety outcomes. CONCLUSION: In this analysis of 9 RCTs in patients with AIS, TNK 0.25 mg/kg was comparable to alteplase 0.9 mg/kg from the perspective of efficacy outcomes and safety outcomes after thrombolysis within 4.5 h of AIS occurrence.

Comparing Low- or Standard-Dose Alteplase in Endovascular Thrombectomy: Insights From a Nationwide Registry.

BACKGROUND: Timely intravenous thrombolysis and endovascular thrombectomy are the standard reperfusion treatments for large vessel occlusion stroke. Currently, it is unknown whether a low-dose thrombolytic agent (0.6 mg/kg alteplase) can offer similar efficacy to the standard dose (0.9 mg/kg alteplase). METHODS: We enrolled consecutive patients in the multicenter Taiwan Registry of Endovascular Thrombectomy for Acute Ischemic Stroke who had received combined thrombolysis (within 4.5 hours of onset) and thrombectomy treatment from January 2019 to April 2023. The choice of low- or standard-dose alteplase was based on the physician's discretion. The outcomes included successful reperfusion (modified Thrombolysis in Cerebral Infarction score, 2b-3), symptomatic intracerebral hemorrhage, 90-day modified Rankin Scale score, and 90-day mortality. The outcomes between the 2 groups were compared using multivariable logistic regression and inverse probability of treatment weighting-adjusted analysis. RESULTS: Among the 2242 patients in the Taiwan Registry of Endovascular Thrombectomy for Acute Ischemic Stroke, 734 (33%) received intravenous alteplase. Patients in the low-dose group (n=360) were older, had more women, more atrial fibrillation, and longer onset-to-needle time compared with the standard-dose group (n=374). In comparison to low-dose alteplase, standard-dose alteplase was associated with a lower rate of successful reperfusion (81% versus 87%; adjusted odds ratio, 0.63 [95% CI, 0.40-0.98]), a numerically higher incidence of symptomatic intracerebral hemorrhage (6.7% versus 3.9%; adjusted odds ratio, 1.81 [95% CI, 0.88-3.69]), but better 90-day modified Rankin Scale score (functional independence [modified Rankin Scale score, 0-2], 47% versus 31%; adjusted odds ratio, 1.91 [95% CI, 1.28-2.86]), and a numerically lower mortality rate (9% versus 15%; adjusted odds ratio, 0.73 [95% CI, 0.43-1.25]) after adjusting for covariates. Similar results were observed in the inverse probability of treatment weighting-adjusted models. The results were consistent across predefined subgroups and age strata. CONCLUSIONS: Despite the lower rate of successful reperfusion and higher risk of symptomatic intracerebral hemorrhage with standard-dose alteplase, standard-dose alteplase was associated with a better functional outcome in patients receiving combined thrombolysis and thrombectomy.

Ultrasound-assisted endovascular thrombolysis versus large-bore thrombectomy in acute intermediate-high risk pulmonary embolism: The propensity-matched EKNARI cohort study.

BACKGROUND: Ultrasound-assisted thrombolysis (USAT) and large-bore-thrombectomy (LBT) are under investigation for the treatment of intermediate-high and high-risk pulmonary embolisms (PE). Comparative studies investigating both devices are scarce. AIMS: This study aimed to compare the safety and efficacy of the two most frequently used devices for treatment of acute PE. METHODS: This multicenter, retrospective study included 125 patients undergoing LBT or USAT for intermediate- or high-risk PE between 2019 and 2023. Nearest neighbor propensity matching with logistic regression was used to achieve balance on potential confounders. The primary outcome was the change in the right to left ventricular (RV/LV) ratio between baseline and 24 h. RESULTS: A total of 125 patients were included. After propensity score matching, 95 patients remained in the sample, of which 69 (73%) underwent USAT and 26 (27%) LBT. The RV/LV ratio decrease between baseline and 24 h was greater in the LBT than in the USAT group (adjusted between-group difference: -0.10, 95% CI: -0.16 to -0.04; p = 0.001). Both procedures were safe and adverse events occurred rarely (10% following USAT vs. 4% following LBT; p = 0.439). CONCLUSION: In acute intermediate-high and high-risk PE, both LBT and USAT were feasible and safe. The reduction in RV/LV ratio was greater following LBT than USAT. Further randomized controlled trials are needed to confirm these findings.

In silico study of combination thrombolytic therapy with alteplase and mutant pro-urokinase for fibrinolysis in ischemic stroke.

The synergistic advantage of combining tissue plasminogen activator (tPA) with pro-urokinase (proUK) for thrombolysis has been demonstrated in several in vitro experiments, and a single site proUK mutant (m-proUK) has been developed for better stability in plasma. Based on these studies, combination thrombolytic therapy with intravenous tPA and m-proUK has been suggested as a promising treatment for patients with ischemic stroke. This paper evaluates the efficacy and safety of the dual therapy by computational simulations of pharmacokinetics and pharmacodynamics coupled with a local fibrinolysis model. Seven dose regimens are simulated and compared with the standard intravenous tPA monotherapy. Our simulation results provide more insights into the complementary reaction mechanisms of tPA and m-proUK during clot lysis and demonstrate that the dual therapy can achieve a similar recanalization time (about 50 min) to tPA monotherapy, while keeping the circulating fibrinogen level within a normal range. Specifically, our results show that for all dual therapies with a 5 mg tPA bolus, the plasma concentration of fibrinogen remains stable at around 7.5 µM after a slow depletion over 50 min, whereas a rapid depletion of circulating fibrinogen (to 5 µM) is observed with the standard tPA therapy, indicating the potential advantage of dual therapy in reducing the risk of intracranial hemorrhage. Through simulations of varying dose combinations, it has been found that increasing tPA bolus can significantly affect fibrinogen level but only moderately improves recanalization time. Conversely, m-proUK doses and infusion duration exhibit a mild impact on fibrinogen level but significantly affect recanalization time. Therefore, future optimization of dose regimen should focus on limiting the tPA bolus while adjusting m-proUK dosage and infusion rate. Such adjustments could potentially maximize the therapeutic advantages of this combination therapy for ischemic stroke treatment.

Use of Ultrasound-Assisted, Catheter-Directed Thrombolysis in a Patient With High-Risk Pulmonary Embolism.

High-risk pulmonary embolism (PE) is a complex clinical entity associated with high mortality rates. Ultrasound-assisted, catheter-directed thrombolysis, typically used for intermediate-risk PE, may be a viable treatment approach for high-risk PE, particularly in patients at increased risk for major bleeding. This report describes a case in which ultrasound-assisted, catheter-directed thrombolysis was successfully used to treat high-risk PE in a female patient with extensive peritoneal metastases from gastric adenocarcinoma. Other examples from the literature, in which ultrasound-assisted, catheter-directed thrombolysis was used to treat high-risk PE, are also provided.

Tenecteplase for Stroke at 4.5 to 24 Hours with Perfusion-Imaging Selection.

BACKGROUND: Thrombolytic agents, including tenecteplase, are generally used within 4.5 hours after the onset of stroke symptoms. Information on whether tenecteplase confers benefit beyond 4.5 hours is limited. METHODS: We conducted a multicenter, double-blind, randomized, placebo-controlled trial involving patients with ischemic stroke to compare tenecteplase (0.25 mg per kilogram of body weight, up to 25 mg) with placebo administered 4.5 to 24 hours after the time that the patient was last known to be well. Patients had to have evidence of occlusion of the middle cerebral artery or internal carotid artery and salvageable tissue as determined on perfusion imaging. The primary outcome was the ordinal score on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability and a score of 6 indicating death) at day 90. Safety outcomes included death and symptomatic intracranial hemorrhage. RESULTS: The trial enrolled 458 patients, 77.3% of whom subsequently underwent thrombectomy; 228 patients were assigned to receive tenecteplase, and 230 to receive placebo. The median time between the time the patient was last known to be well and randomization was approximately 12 hours in the tenecteplase group and approximately 13 hours in the placebo group. The median score on the modified Rankin scale at 90 days was 3 in each group. The adjusted common odds ratio for the distribution of scores on the modified Rankin scale at 90 days for tenecteplase as compared with placebo was 1.13 (95% confidence interval, 0.82 to 1.57; P = 0.45). In the safety population, mortality at 90 days was 19.7% in the tenecteplase group and 18.2% in the placebo group, and the incidence of symptomatic intracranial hemorrhage was 3.2% and 2.3%, respectively. CONCLUSIONS: Tenecteplase therapy that was initiated 4.5 to 24 hours after stroke onset in patients with occlusions of the middle cerebral artery or internal carotid artery, most of whom had undergone endovascular thrombectomy, did not result in better clinical outcomes than those with placebo. The incidence of symptomatic intracerebral hemorrhage was similar in the two groups. (Funded by Genentech; TIMELESS ClinicalTrials.gov number, NCT03785678.).

Tenecteplase-associated orolingual angioedema: A case report and literature review.

PURPOSE: Orolingual angioedema (OA) secondary to administration of thrombolytic therapy is a rare, but serious, known adverse effect. Despite the lack of robust evidence for their use, C1 esterase inhibitors are recommended by guidelines for the treatment of refractory thrombolytic-associated OA. This report highlights the use of a C1 esterase inhibitor in a patient with tenecteplase-associated OA unresolved by antihistamine and corticosteroid therapy. SUMMARY: A 67-year-old white male with a history of hypertension managed with lisinopril presented to the emergency department with acute onset of slurred speech and left-sided hemiparesis. Following workup, an outside hospital's neurology stroke team suspected an acute infarct and determined the patient to be a candidate for tenecteplase. Approximately 1 hour after tenecteplase administration, the patient began complaining of dyspnea and mild oral angioedema. Immediate interventions for OA management included intravenous therapy with dexamethasone 10 mg, diphenhydramine 25 mg, and famotidine 20 mg. After an additional 30 minutes, the patient's OA symptoms continued to progress and a C1 esterase inhibitor (Berinert) was administered. Shortly after administration of the C1 esterase inhibitor, the patient's symptoms continued to worsen, ultimately leading to endotracheal intubation. Following intubation, symptom improvement was noted, and the patient was safely extubated after 30 hours. CONCLUSION: Although rare, OA is a potentially life-threatening complication of tenecteplase therapy and requires prompt pharmacological intervention to optimize patient outcomes. Currently, no single agent or treatment algorithm exists that has shown significant efficacy or safety in the setting of thrombolytic-associated OA. Until data are available for C1 esterase inhibitors in this application, these inhibitors should only be considered if there is continued symptom progression after intravenous administration of corticosteroids and antihistamines.

Magnetic Resonance Imaging-Guided Intravenous Thrombolysis in Cardioembolic Stroke Patients With Unknown Time of Onset　- Subanalysis of the THAWS Randomized Control Trial.

BACKGROUND: We investigated the clinical effect of intravenous thrombolysis using a magnetic resonance imaging (MRI)-guided approach in cardioembolic stroke (CE) patients with unknown time of onset.Methods and Results: This subanalysis of the THAWS trial assessed the efficacy and safety of alteplase 0.6 mg/kg in CE patients with unknown time of onset and showing diffusion-weighted imaging-fluid-attenuated inversion recovery mismatch. Patients were classified as CE and non-CE using the SSS-TOAST classification system during the acute period. The efficacy outcome was a modified Rankin Scale score of 0-1 at 90 days. In all, 126 patients from the THAWS trial were included in this study, of whom 45 (35.7%) were diagnosed with CE. In the CE group, a favorable outcome was numerically more frequent in the alteplase than control group (52% vs. 35%; adjusted odds ratio [aOR] 2.25; 95% confidence interval [CI] 0.50-9.99). However, in the non-CE group, favorable outcomes were comparable between the alteplase and control groups (44% vs. 55%, respectively; aOR 0.39; 95% CI 0.12-1.21). Treatment-by-cohort interaction for a favorable outcome was modestly significant between the CE and non-CE groups (P=0.069). In the CE group, no patients experienced symptomatic intracranial hemorrhage (ICH) or parenchymal hematoma Type II following thrombolysis. CONCLUSIONS: When an MRI-guided approach is used, CE patients with unknown time of onset appear to be suitable candidates for thrombolysis.

Thrombolytic Treatment in Wake-Up Stroke: A Propensity Score-Matched Analysis of Treatment Effectiveness in the Norwegian Stroke Registry.

BACKGROUND: Previous clinical trials found improved outcome of thrombolytic treatment in patients with ischemic wake-up stroke (WUS) selected by advanced imaging techniques. The authors assessed the effectiveness of thrombolytic treatment in patients with WUS in a nationwide stroke registry. METHODS AND RESULTS: Using propensity score matching, the authors assessed the effectiveness and safety of thrombolytic treatment versus no thrombolytic treatment in 726 patients (363 matched pairs) with WUS in the Norwegian Stroke Registry in 2014 to 2019. Thrombolytic treatment in WUS versus known-onset stroke was compared in 730 patients (365 matched pairs). Functional outcomes were assessed by the modified Rankin Scale (mRS) at 3 months. A significant benefit of thrombolytic treatment in WUS was seen in ordinal analysis (odds ratio [OR], 1.48 [95% CI, 1.15-1.91]; P=0.003) and for mRS 0 to 2 (OR, 1.81 [95% CI, 1.29-2.52]; P=0.001) but not for mRS 0 or 1 (OR, 1.32 [95% CI, 1.00-1.74]; P=0.050). The proportion of patients with mRS 0 or 1 was lower in patients with WUS who underwent thrombolysis versus those with known-onset stroke (50.4% versus 59.5%; OR, 0.69 [95% CI, 0.52-0.93]; P=0.013), while outcomes were similar between groups for mRS 0 to 2 and ordinal analysis. Symptomatic intracranial hemorrhage after thrombolytic treatment occurred in 4.4% of patients with WUS and 3.9% of patients with known-onset stroke (OR, 1.14 [95% CI, 0.54-2.41]; P=0.726). CONCLUSIONS: Thrombolytic treatment in patients with WUS was associated with improved functional outcome compared with patients with no thrombolytic treatment and was not associated with increased rates of symptomatic intracranial hemorrhage compared with known-onset stroke. The results indicate that thrombolytic treatment is effective and safe in WUS in a real-life setting.