-
JAMA Jun 2023Intravenous thrombolysis is increasingly used in patients with minor stroke, but its benefit in patients with minor nondisabling stroke is unknown. (Comparative Study)
Comparative Study Randomized Controlled Trial
IMPORTANCE
Intravenous thrombolysis is increasingly used in patients with minor stroke, but its benefit in patients with minor nondisabling stroke is unknown.
OBJECTIVE
To investigate whether dual antiplatelet therapy (DAPT) is noninferior to intravenous thrombolysis among patients with minor nondisabling acute ischemic stroke.
DESIGN, SETTING, AND PARTICIPANTS
This multicenter, open-label, blinded end point, noninferiority randomized clinical trial included 760 patients with acute minor nondisabling stroke (National Institutes of Health Stroke Scale [NIHSS] score ≤5, with ≤1 point on the NIHSS in several key single-item scores; scale range, 0-42). The trial was conducted at 38 hospitals in China from October 2018 through April 2022. The final follow-up was on July 18, 2022.
INTERVENTIONS
Eligible patients were randomized within 4.5 hours of symptom onset to the DAPT group (n = 393), who received 300 mg of clopidogrel on the first day followed by 75 mg daily for 12 (±2) days, 100 mg of aspirin on the first day followed by 100 mg daily for 12 (±2) days, and guideline-based antiplatelet treatment until 90 days, or the alteplase group (n = 367), who received intravenous alteplase (0.9 mg/kg; maximum dose, 90 mg) followed by guideline-based antiplatelet treatment beginning 24 hours after receipt of alteplase.
MAIN OUTCOMES AND MEASURES
The primary end point was excellent functional outcome, defined as a modified Rankin Scale score of 0 or 1 (range, 0-6), at 90 days. The noninferiority of DAPT to alteplase was defined on the basis of a lower boundary of the 1-sided 97.5% CI of the risk difference greater than or equal to -4.5% (noninferiority margin) based on a full analysis set, which included all randomized participants with at least 1 efficacy evaluation, regardless of treatment group. The 90-day end points were assessed in a blinded manner. A safety end point was symptomatic intracerebral hemorrhage up to 90 days.
RESULTS
Among 760 eligible randomized patients (median [IQR] age, 64 [57-71] years; 223 [31.0%] women; median [IQR] NIHSS score, 2 [1-3]), 719 (94.6%) completed the trial. At 90 days, 93.8% of patients (346/369) in the DAPT group and 91.4% (320/350) in the alteplase group had an excellent functional outcome (risk difference, 2.3% [95% CI, -1.5% to 6.2%]; crude relative risk, 1.38 [95% CI, 0.81-2.32]). The unadjusted lower limit of the 1-sided 97.5% CI was -1.5%, which is larger than the -4.5% noninferiority margin (P for noninferiority <.001). Symptomatic intracerebral hemorrhage at 90 days occurred in 1 of 371 participants (0.3%) in the DAPT group and 3 of 351 (0.9%) in the alteplase group.
CONCLUSIONS AND RELEVANCE
Among patients with minor nondisabling acute ischemic stroke presenting within 4.5 hours of symptom onset, DAPT was noninferior to intravenous alteplase with regard to excellent functional outcome at 90 days.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03661411.
Topics: Female; Humans; Male; Middle Aged; Cerebral Hemorrhage; Fibrinolytic Agents; Ischemic Stroke; Platelet Aggregation Inhibitors; Stroke; Tissue Plasminogen Activator; Treatment Outcome; Drug Therapy, Combination; Thrombolytic Therapy; Administration, Intravenous; Clopidogrel; Aspirin; Follow-Up Studies; Aged; Recovery of Function
PubMed: 37367978
DOI: 10.1001/jama.2023.7827 -
Ophthalmology Sep 2023To compare the efficacy and the safety of submacular hemorrhage (SMH) management using either surgical pars plana vitrectomy (PPV) or pneumatic displacement (PD) with... (Randomized Controlled Trial)
Randomized Controlled Trial
Surgery, Tissue Plasminogen Activator, Antiangiogenic Agents, and Age-Related Macular Degeneration Study: A Randomized Controlled Trial for Submacular Hemorrhage Secondary to Age-Related Macular Degeneration.
PURPOSE
To compare the efficacy and the safety of submacular hemorrhage (SMH) management using either surgical pars plana vitrectomy (PPV) or pneumatic displacement (PD) with tissue plasminogen activator (tPA) and vascular endothelial growth factor (VEGF) inhibitor added to each arm.
DESIGN
Randomized, open-label, multicenter superiority study.
PARTICIPANTS
Ninety patients with neovascular age-related macular degeneration (nAMD) 50 years of age or older with recent SMH (≤ 14 days) of more than 2 optic disc areas and predominantly overlying the retinal pigment epithelium.
METHODS
Patients were assigned randomly to surgery (PPV, subretinal tPA [maximum, 0.5 ml/50 μg], and 20% sulfur hexafluoride [SF] tamponade) or PD (0.05 ml intravitreal tPA [50 μg] and 0.3 ml intravitreal pure SF). Both groups were asked to maintain a head upright position with the face forward at 45° for 3 days after intervention and received 0.5 mg intravitreal ranibizumab at the end of the intervention, at months 1 and 2, as the loading phase, and then on a pro re nata regimen during a 6-month follow-up.
MAIN OUTCOME MEASURES
The primary efficacy endpoint was mean best-corrected visual acuity (VA) change at month 3. The secondary endpoints were mean VA change at month 6, 25-item National Eye Institute Visual Function Questionnaire composite score value at months 3 and 6, number of anti-VEGF injections, and complications during the 6-month follow-up.
RESULTS
Of the 90 patients randomized, 78 patients (86.7%) completed the 3-month efficacy endpoint visit. The mean VA change from baseline to month 3 in the surgery group (+16.8 letters [95% confidence interval (CI), 8.7-24.9 letters]) was not significantly superior to that in the PD group (+16.4 letters [95% CI, 7.1-25.7 letters]; adjusted difference β, 1.9 [-11.0; 14.9]; P = 0.767). Both groups achieved similar secondary outcomes at month 6. No unexpected ocular safety concerns were observed in either group.
CONCLUSIONS
Surgery did not yield superior visual gain nor additional benefit for SMH secondary to nAMD compared with PD at 3 months, with intravitreal anti-VEGF added to each arm. Both treatment strategies lead to a clinical improvement of VA without safety concerns for SMH over 6 months. Both design and results of the trial cannot be used to establish equivalence between treatments.
FINANCIAL DISCLOSURE(S)
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Topics: Humans; Middle Aged; Infant, Newborn; Tissue Plasminogen Activator; Angiogenesis Inhibitors; Fibrinolytic Agents; Vascular Endothelial Growth Factor A; Ranibizumab; Retinal Hemorrhage; Macular Degeneration; Retinal Pigment Epithelium; Intravitreal Injections
PubMed: 37088447
DOI: 10.1016/j.ophtha.2023.04.014 -
Advanced Science (Weinheim,... Aug 2023The circadian clock in animals and humans plays crucial roles in multiple physiological processes. Disruption of circadian homeostasis causes detrimental effects. Here,...
The circadian clock in animals and humans plays crucial roles in multiple physiological processes. Disruption of circadian homeostasis causes detrimental effects. Here, it is demonstrated that the disruption of the circadian rhythm by genetic deletion of mouse brain and muscle ARNT-like 1 (Bmal1) gene, coding for the key clock transcription factor, augments an exacerbated fibrotic phenotype in various tumors. Accretion of cancer-associated fibroblasts (CAFs), especially the alpha smooth muscle actin positive myoCAFs, accelerates tumor growth rates and metastatic potentials. Mechanistically, deletion of Bmal1 abrogates expression of its transcriptionally targeted plasminogen activator inhibitor-1 (PAI-1). Consequently, decreased levels of PAI-1 in the tumor microenvironment instigate plasmin activation through upregulation of tissue plasminogen activator and urokinase plasminogen activator. The activated plasmin converts latent TGF-β into its activated form, which potently induces tumor fibrosis and the transition of CAFs into myoCAFs, the latter promoting cancer metastasis. Pharmacological inhibition of the TGF-β signaling largely ablates the metastatic potentials of colorectal cancer, pancreatic ductal adenocarcinoma, and hepatocellular carcinoma. Together, these data provide novel mechanistic insights into disruption of the circadian clock in tumor growth and metastasis. It is reasonably speculated that normalization of the circadian rhythm in patients provides a novel paradigm for cancer therapy.
Topics: Mice; Humans; Animals; Transforming Growth Factor beta; Tissue Plasminogen Activator; Fibrinolysin; Plasminogen Activator Inhibitor 1; Liver Neoplasms; Muscles; Brain; Tumor Microenvironment
PubMed: 37330661
DOI: 10.1002/advs.202301505 -
Journal of Thrombosis and Haemostasis :... Dec 2023Fibrinolysis is the system primarily responsible for removal of fibrin deposits and blood clots in the vasculature. The terminal enzyme in the pathway, plasmin, is... (Review)
Review
Fibrinolysis is the system primarily responsible for removal of fibrin deposits and blood clots in the vasculature. The terminal enzyme in the pathway, plasmin, is formed from its circulating precursor, plasminogen. Fibrin is by far the most legendary substrate, but plasmin is notoriously prolific and is known to cleave many other proteins and participate in the activation of other proteolytic systems. Fibrinolysis is often overshadowed by the coagulation system and viewed as a simplistic poorer relation. However, the primordial plasminogen activators evolved alongside the complement system, approximately 70 million years before coagulation saw the light of day. It is highly likely that the plasminogen activation system evolved with its roots in primordial immunity. Almost all immune cells harbor at least one of a dozen plasminogen receptors that allow plasmin formation on the cell surface that in turn modulates immune cell behavior. Similarly, numerous pathogens express their own plasminogen activators or contain surface proteins that provide binding sites for host plasminogen. The fibrinolytic system has been harnessed for clinical medicine for many decades with the development of thrombolytic drugs and antifibrinolytic agents. Our refined understanding and appreciation of the fibrinolytic system and its alliance with infection and immunity and beyond are paving the way for new developments and interest in novel therapeutics and applications. One must ponder as to whether the nomenclature of the system hampered our understanding, by focusing on fibrin, rather than the complex myriad of interactions and substrates of the plasminogen activation system.
Topics: Humans; Fibrinolysis; Fibrinolysin; Plasminogen Activators; Plasminogen; Fibrin; Serine Proteases
PubMed: 38000850
DOI: 10.1016/j.jtha.2023.09.012 -
JAMA Neurology Jul 2023Symptomatic intracranial hemorrhage (sICH) is a serious complication of stroke thrombolytic therapy. Many stroke centers have adopted 0.25-mg/kg tenecteplase instead of... (Observational Study)
Observational Study
Symptomatic Intracranial Hemorrhage With Tenecteplase vs Alteplase in Patients With Acute Ischemic Stroke: The Comparative Effectiveness of Routine Tenecteplase vs Alteplase in Acute Ischemic Stroke (CERTAIN) Collaboration.
IMPORTANCE
Symptomatic intracranial hemorrhage (sICH) is a serious complication of stroke thrombolytic therapy. Many stroke centers have adopted 0.25-mg/kg tenecteplase instead of alteplase for stroke thrombolysis based on evidence from randomized comparisons to alteplase as well as for its practical advantages. There have been no significant differences in symptomatic intracranial hemorrhage (sICH) reported from randomized clinical trials or published case series for the 0.25-mg/Kg dose.
OBJECTIVE
To assess the risk of sICH following ischemic stroke in patients treated with tenecteplase compared to those treated with alteplase.
DESIGN, SETTING, AND PARTICIPANTS
This was a retrospective observational study using data from the large multicenter international Comparative Effectiveness of Routine Tenecteplase vs Alteplase in Acute Ischemic Stroke (CERTAIN) collaboration comprising deidentified data on patients with ischemic stroke treated with intravenous thrombolysis. Data from more than 100 hospitals in New Zealand, Australia, and the US that used alteplase or tenecteplase for patients treated between July 1, 2018, and June 30, 2021, were included for analysis. Participating centers included a mix of nonthrombectomy- and thrombectomy-capacity comprehensive stroke centers. Standardized data were abstracted and harmonized from local or regional clinical registries. Consecutive patients with acute ischemic stroke who were considered eligible and received thrombolysis at the participating stroke registries during the study period were included. All 9238 patients who received thrombolysis were included in this retrospective analysis.
MAIN OUTCOMES AND MEASURES
sICH was defined as clinical worsening of at least 4 points on the National Institutes of Health Stroke Scale (NIHSS), attributed to parenchymal hematoma, subarachnoid, or intraventricular hemorrhage. Differences between tenecteplase and alteplase in the risk of sICH were assessed using logistic regression, adjusted for age, sex, NIHSS score, and thrombectomy.
RESULTS
Of the 9238 patients included in the analysis, the median (IQR) age was 71 (59-80) years, and 4449 patients (48%) were female. Tenecteplase was administered to 1925 patients. The tenecteplase group was older (median [IQR], 73 [61-81] years vs 70 [58-80] years; P < .001), more likely to be male (1034 of 7313 [54%] vs 3755 of 1925 [51%]; P < .01), had higher NIHSS scores (median [IQR], 9 [5-17] vs 7 [4-14]; P < .001), and more frequently underwent endovascular thrombectomy (38% vs 20%; P < .001). The proportion of patients with sICH was 1.8% for tenecteplase and 3.6% for alteplase (P < .001), with an adjusted odds ratio (aOR) of 0.42 (95% CI, 0.30-0.58; P < .01). Similar results were observed in both thrombectomy and nonthrombectomy subgroups.
CONCLUSIONS AND RELEVANCE
In this large study, ischemic stroke treatment with 0.25-mg/kg tenecteplase was associated with lower odds of sICH than treatment with alteplase. The results provide evidence supporting the safety of tenecteplase for stroke thrombolysis in real-world clinical practice.
Topics: Humans; Male; Female; Aged; Aged, 80 and over; Tissue Plasminogen Activator; Tenecteplase; Ischemic Stroke; Retrospective Studies; Brain Ischemia; Fibrinolytic Agents; Stroke; Intracranial Hemorrhages; Treatment Outcome
PubMed: 37252708
DOI: 10.1001/jamaneurol.2023.1449