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Pharmacology 2023Thrombolytic agents and anticoagulants are the two classes of medication used in the treatment of acute pulmonary embolism (PE). There is continuous renewal and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Thrombolytic agents and anticoagulants are the two classes of medication used in the treatment of acute pulmonary embolism (PE). There is continuous renewal and iteration of thrombolytic agents, and the efficacy and adverse effects of different agents have different effects on PE due to their different mechanisms of action.
OBJECTIVES
The aim of the study was to evaluate the efficacy and safety of different thrombolytic agents in the treatment of all types of acute PE: hemodynamically unstable PE (massive PE) and hemodynamically stable PE (submassive PE and low-risk PE), using a network meta-analysis.
METHODS
A search was conducted of the following databases: PubMed, The Cochrane Library, Embase, and Web of Science to collect randomized controlled trials (RCTs) comparing thrombolytic agents with heparin or other thrombolytic agents in patients with acute PE; the clinical outcomes included patient mortality, recurrent PE, pulmonary artery systolic pressure (PASP) after treatment, and major and minor bleeding. The measurement duration of outcome indicators was the longest follow-up period. Thereafter, a network meta-analysis was performed using a Bayesian network framework.
RESULTS
A total of 29 RCTs (3,067 patients) were included, of which 6 studies (304 patients) were massive PE, 14 studies (2,173 patients) were submassive PE, 1 study (83 patients) included massive and submassive PE, and 8 studies (507 patients) were PE of unknown type. The treatment regimens included thrombolytic therapy (alteplase, reteplase, tenecteplase, streptokinase, and urokinase) and anticoagulant therapy alone. The results showed that the mortality using thrombolytic agents (except tenecteplase) was significantly lower compared with heparin. The recurrence of PE with alteplase was significantly lower compared with heparin (RR = 0.23, 95% CI, 0.04, 0.65). The PASP after using alteplase was significantly lower compared with heparin (mean difference = -11.36, 95% CI, -21.45, -1.56). Compared with heparin, the incidence of minor bleeding associated with tenecteplase was higher (RR = 3.27, 95% CI, 1.36, 7.39); compared with streptokinase, the incidence of minor bleeding associated with tenecteplase was higher (RR = 3.22, 95% CI, 1.01, 11.10).
CONCLUSION
For patients with acute PE, four thrombolytic agents (alteplase, reteplase, streptokinase, and urokinase) appeared to be superior in efficacy compared with anticoagulants alone due to a reduction in mortality and no increase in bleeding risk. Alteplase may be a better choice because it not only reduced mortality but also reduced PE recurrence rate and treated PASP. Tenecteplase did not reduce mortality compared with anticoagulants alone and may not be a good choice of thrombolytic agent due to an increase in minor bleeding compared with streptokinase and anticoagulants alone. Thrombolytic drugs should be rationally selected to optimize the thrombolytic regimen and achieve as good a balance as possible between thrombolysis and bleeding.
Topics: Humans; Fibrinolytic Agents; Tissue Plasminogen Activator; Tenecteplase; Urokinase-Type Plasminogen Activator; Network Meta-Analysis; Pulmonary Embolism; Heparin; Streptokinase; Hemorrhage; Anticoagulants
PubMed: 36603558
DOI: 10.1159/000527668 -
The New England Journal of Medicine Mar 2012Intravenous alteplase is the only approved treatment for acute ischemic stroke. Tenecteplase, a genetically engineered mutant tissue plasminogen activator, is an... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Intravenous alteplase is the only approved treatment for acute ischemic stroke. Tenecteplase, a genetically engineered mutant tissue plasminogen activator, is an alternative thrombolytic agent.
METHODS
In this phase 2B trial, we randomly assigned 75 patients to receive alteplase (0.9 mg per kilogram of body weight) or tenecteplase (0.1 mg per kilogram or 0.25 mg per kilogram) less than 6 hours after the onset of ischemic stroke. To favor the selection of patients most likely to benefit from thrombolytic therapy, the eligibility criteria were a perfusion lesion at least 20% greater than the infarct core on computed tomographic (CT) perfusion imaging at baseline and an associated vessel occlusion on CT angiography. The coprimary end points were the proportion of the perfusion lesion that was reperfused at 24 hours on perfusion-weighted magnetic resonance imaging and the extent of clinical improvement at 24 hours as assessed on the National Institutes of Health Stroke Scale (NIHSS, a 42-point scale on which higher scores indicate more severe neurologic deficits).
RESULTS
The three treatment groups each comprised 25 patients. The mean (±SD) NIHSS score at baseline for all patients was 14.4±2.6, and the time to treatment was 2.9±0.8 hours. Together, the two tenecteplase groups had greater reperfusion (P=0.004) and clinical improvement (P<0.001) at 24 hours than the alteplase group. There were no significant between-group differences in intracranial bleeding or other serious adverse events. The higher dose of tenecteplase (0.25 mg per kilogram) was superior to the lower dose and to alteplase for all efficacy outcomes, including absence of serious disability at 90 days (in 72% of patients, vs. 40% with alteplase; P=0.02).
CONCLUSIONS
Tenecteplase was associated with significantly better reperfusion and clinical outcomes than alteplase in patients with stroke who were selected on the basis of CT perfusion imaging. (Funded by the Australian National Health and Medical Research Council; Australia New Zealand Clinical Trials Registry number, ACTRN12608000466347.).
Topics: Aged; Brain Ischemia; Dose-Response Relationship, Drug; Female; Fibrinolytic Agents; Humans; Male; Middle Aged; Single-Blind Method; Stroke; Tenecteplase; Tissue Plasminogen Activator; Treatment Outcome
PubMed: 22435369
DOI: 10.1056/NEJMoa1109842 -
Neurotherapeutics : the Journal of the... Apr 2023Alteplase has been the primary thrombolytic used in the treatment of acute ischemic stroke since thrombolysis was first established as an effective treatment of acute... (Review)
Review
Alteplase has been the primary thrombolytic used in the treatment of acute ischemic stroke since thrombolysis was first established as an effective treatment of acute ischemic stroke in 1995. Tenecteplase, a genetically modified tissue plasminogen activator, has gained attention as an attractive alternative to alteplase given its practical workflow advantages and possible superior efficacy in large vessel recanalization. As more data is analyzed both from randomized trials and non-randomized patient registries, there is mounting support that tenecteplase appears to be at least equally, if not more, safe and potentially more effective than alteplase in the treatment of acute ischemic stroke. Randomized trials investigating tenecteplase in the delayed treatment window and with thrombectomy are ongoing, and their results are eagerly awaited. This paper provides an overview of completed and ongoing randomized trials and nonrandomized studies analyzing tenecteplase in the treatment of acute ischemic stroke. Results reviewed support the safe use of tenecteplase in clinical practice.
Topics: Humans; Tissue Plasminogen Activator; Tenecteplase; Ischemic Stroke; Stroke; Brain Ischemia; Fibrinolytic Agents
PubMed: 37273127
DOI: 10.1007/s13311-023-01391-3 -
Journal of the American Heart... May 2024Although intravenous thrombolysis with alteplase remains the primary treatment for acute ischemic stroke, tenecteplase has shown potential advantages over alteplase.... (Review)
Review
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.
Topics: Tenecteplase; Humans; Fibrinolytic Agents; Ischemic Stroke; Thrombolytic Therapy; Tissue Plasminogen Activator; Treatment Outcome; Animals
PubMed: 38686848
DOI: 10.1161/JAHA.123.031692 -
Journal of Vascular Surgery Dec 2015
Topics: Female; Fibrinolytic Agents; Humans; Male; Thrombolytic Therapy; Tissue Plasminogen Activator
PubMed: 26412435
DOI: 10.1016/j.jvs.2015.07.089 -
Indian Heart Journal 2014
Topics: Female; Fibrinolytic Agents; Humans; Male; Myocardial Infarction; Tissue Plasminogen Activator
PubMed: 24814131
DOI: 10.1016/j.ihj.2014.02.013 -
Cells May 2020The activation of the nuclear factor-κB (NF-κB) pathway plays a central role in the initiation and progression of inflammation, which contributes to the pathogenesis... (Review)
Review
The activation of the nuclear factor-κB (NF-κB) pathway plays a central role in the initiation and progression of inflammation, which contributes to the pathogenesis and progression of various human diseases including kidney, brain, and other diseases. Tissue plasminogen activator (tPA), a serine protease regulating homeostasis of blood coagulation, fibrinolysis, and matrix degradation, has been shown to act as a cytokine to trigger profound receptor-mediated intracellular events, modulate the NF-κB pathway, and mediate organ dysfunction and injury. In this review, we focus on the current understanding of NF-κB and tPA signaling in the development and progression of kidney disease. Their roles in the nervous and cardiovascular system are also briefly discussed.
Topics: Animals; Humans; Inflammation; Kidney Diseases; Macrophages; NF-kappa B; Signal Transduction; Tissue Plasminogen Activator
PubMed: 32485860
DOI: 10.3390/cells9061348 -
Blood Advances Dec 2021Ultrasound-facilitated catheter-directed thrombolysis is used with low-dose alteplase to treat pulmonary embolism. This reduces the risk of bleeding that accompanies...
Ultrasound-facilitated catheter-directed thrombolysis is used with low-dose alteplase to treat pulmonary embolism. This reduces the risk of bleeding that accompanies systemic administration of higher alteplase doses. Some studies suggest that alteplase given over 2 to 6 hours is safe and effective, but there are few data to support the stability of alteplase under these conditions. Therefore, we undertook this in vitro study to determine the duration of alteplase stability. Alteplase was prepared in solutions of 8 mg in 100 mL, 6 mg in 150 mL, and 8 mg in 200 mL. Solutions were administered through the EkoSonic Endovascular System (with and without ultrasound) to simulate administration over 2, 4, and 6 hours. Alteplase was assessed with reversed-phase high-performance liquid chromatography (RP-HPLC). Assays were performed at time 0 and at 30-minute intervals during simulated infusion. An enzyme-linked immunosorbent assay was used to measure alteplase concentrations at time 0 and at 15-minute intervals during simulated infusion. By using RP-HPLC in the absence of ultrasound, the alteplase concentration remained within 1% of the original concentration through 120, 240, and 360 minutes of infusion. By using RP-HPLC for measurement, alteplase in the presence of ultrasound degraded steadily over time to ∼90% of its original amount in 120 minutes, ∼80% in 240 minutes, and ∼70% in 360 minutes. The remaining alteplase was available for enzymatic activity. Alteplase solutions of 0.04 and 0.08 mg/mL degraded steadily over time during simulated ultrasound-facilitated catheter-directed administration. Alteplase that did not degrade remained available for enzymatic activity.
Topics: Catheters; Fibrinolytic Agents; Humans; Pulmonary Embolism; Thrombolytic Therapy; Tissue Plasminogen Activator
PubMed: 34507349
DOI: 10.1182/bloodadvances.2021005001 -
Stroke Dec 2015We compared the fibrinolytic activity of tenecteplase and alteplase in patients with acute ischemic stroke, and explored the association between hypofibrinogenaemia and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND PURPOSE
We compared the fibrinolytic activity of tenecteplase and alteplase in patients with acute ischemic stroke, and explored the association between hypofibrinogenaemia and intracerebral hemorrhage.
METHODS
Venous blood samples from a subgroup of participants in the Alteplase-Tenecteplase Trial Evaluation for Stroke Thrombolysis (ATTEST) study were obtained at pretreatment, 3 to 12 hours, and 24±3 hours post-intravenous thrombolysis for analyses of plasminogen, plasminogen activator inhibitor-1, d-dimer, factor V, fibrinogen, and fibrin(ogen) degradation products, in addition to routine coagulation assays. Related sample Wilcoxon signed-rank tests were used to test the within-group changes, and independent Mann-Whitney tests for between-group differences.
RESULTS
Thirty patients were included (alteplase=14 and tenecteplase=16) with similar baseline demographics. Compared with baseline, alteplase caused significant hypofibrinogenaemia (P=0.002), prolonged prothrombin time (P=0.011), hypoplasminogenaemia (P=0.001), and lower factor V (P=0.002) at 3 to 12 hours after administration with persistent hypofibrinogenaemia at 24 hours (P=0.011), whereas only minor hypoplasminogenaemia (P=0.029) was seen in the tenecteplase group. Tenecteplase consumed less plasminogen (P<0.001) and fibrinogen (P=0.002) compared with alteplase.
CONCLUSIONS
In patients with acute ischemic stroke, alteplase 0.9 mg/kg caused significant disruption of the fibrinolytic system, whereas tenecteplase 0.25 mg/kg did not, consistent with the trend toward lower intracerebral hemorrhage incidence with tenecteplase in the ATTEST study.
CLINICAL TRIAL REGISTRATION
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01472926.
Topics: Aged; Aged, 80 and over; Blood Coagulation; Brain Ischemia; Female; Fibrinolytic Agents; Humans; Male; Middle Aged; Stroke; Tenecteplase; Tissue Plasminogen Activator; Treatment Outcome
PubMed: 26514192
DOI: 10.1161/STROKEAHA.115.011290 -
BMJ Open Sep 2022Endovascular therapy (EVT) has proven to be clinically effective in treating large vessel occlusion acute ischaemic stroke (AIS), either alone or in combination with...
OBJECTIVES
Endovascular therapy (EVT) has proven to be clinically effective in treating large vessel occlusion acute ischaemic stroke (AIS), either alone or in combination with intravenous alteplase. Despite this, there is a limited evidence on the cost-effectiveness of EVT in Thailand and other low-income and middle-income countries. This study aims to assess whether EVT is a cost-effective therapy for AIS, and to estimate the fiscal burden to the Thai government through budget impact analysis.
METHODS
An economic evaluation was performed to compare AIS therapy with and without EVT from a societal perspective. The primary outcome was incremental cost-effectiveness per quality-adjusted life year (QALY) gained. Clinical parameters were derived from both national and international literature, while cost and utility data were collected locally. The analysis applied a cost-effectiveness threshold of 160 000 Baht (~$5000) per QALY, as set by the Thai government.
RESULTS
Both EVT alone and EVT combined with intravenous alteplase, among patients who are ineligible and eligible for intravenous alteplase, respectively, improved health outcomes but incurred additional cost. The combination of EVT and intravenous alteplase was associated with an incremental cost-effectiveness ratio (ICER) of 146 800 THB per QALY gained compared with intravenous alteplase alone, and the ICER of EVT alone compared with supportive care among patients ineligible for intravenous alteplase was estimated at 115 000 THB per QALY gained. Sensitivity analysis showed that the price of EVT has the greatest impact on model outcomes. Over a time horizon of 5 years, the introduction of EVT into the Thai health benefit package would require an additional budget of 887 million THB, assuming 2000 new cases per year.
CONCLUSIONS
EVT represents good value for money in the Thai context, both when provided to patients eligible for intravenous alteplase, and when provided alone to those who are ineligible for intravenous alteplase.
Topics: Brain Ischemia; Cost-Benefit Analysis; Humans; Ischemic Stroke; Quality-Adjusted Life Years; Stroke; Thailand; Tissue Plasminogen Activator
PubMed: 36167373
DOI: 10.1136/bmjopen-2022-064403