-
ARYA Atherosclerosis 2023Primary percutaneous coronary intervention (PPCI) is the gold standard approach to restore blood flow in ST-segment elevation myocardial infarction (STEMI); however, the...
INTRODUCTION
Primary percutaneous coronary intervention (PPCI) is the gold standard approach to restore blood flow in ST-segment elevation myocardial infarction (STEMI); however, the no-reflow phenomenon as a potential complication of PPCI can worsen the outcomes. It has been hypothesized that adjunctive prophylactic intracoronary infusion of low-dose fibrinolytic might improve the PPCI outcomes; however, this theory is a matter of debate. The current study aims to investigate the value of adjunctive prophylactic intracoronary low-dose alteplase to prevent the no-reflow phenomenon in patients with STEMI.
METHOD
This case-control study was conducted on 80 STEMI patients who underwent PPCI. The patients were assigned into the case group who were intervened by 10 mg adjunctive intracoronary alteplase immediately at the end of the balloon angioplasty (n=40) and controls (n=40) who underwent conventional PPCI only. The angioplasty-associated outcomes including final TIMI score, need for no-reflow treatment, ST-segment resolution, post-PPCI complications, and death were compared between the groups.
RESULTS
Alteplase use was accompanied by significantly improved final TIMI flow scores (P-value<0.001) and fewer requirements for no-reflow treatments (P-value<0.001); however, it did not improve the ST-segment resolution (P-value=0.491). The mortality rate and post-angioplasty complications did not differ between the groups (P-value>0.05).
CONCLUSION
Based on the findings of this study, adjunctive infusion of low-dose intracoronary alteplase during PPCI could not efficiently prevent the no-reflow phenomenon. Although the final TIMI flow and need for post-stenting no-reflow treatment improved, ST-segment resolution did not occur dramatically. Given that, this approach requires further investigations and should be considered cautiously.
PubMed: 38883855
DOI: 10.48305/arya.2023.41614.2890 -
Journal of Thoracic Disease May 2024There is no established standard 3 line treatment for patients with advanced non-small cell lung cancer (NSCLC). Although cytotoxic chemotherapeutic agents that are not...
Treatment rationale and protocol design: an investigator-initiated phase II study of combination treatment of nivolumab and TM5614, a PAI-1 inhibitor for previously treated patients with non-small cell lung cancer.
BACKGROUND
There is no established standard 3 line treatment for patients with advanced non-small cell lung cancer (NSCLC). Although cytotoxic chemotherapeutic agents that are not used as 1 or 2 line treatment are administrated as 3 line treatment, their anti-tumor efficacy is insufficient. Anti-programmed death ligand-1 (PD-L1)/programmed death-1 (PD1) treatment is more effective and less toxic than chemotherapy in anti-PD-L1/PD-1 treatment-naïve patients with NSCLC. Therefore, anti-PD-L1/PD-1 therapy is considered an appropriate 3 line treatment. However, the anti-tumor efficacy is limited in patients previously treated with anti-PD-L1/PD-1 antibody. Today, new drugs are needed to increase the efficacy of anti-PD-L1/PD-1 antibodies.
METHODS
This open-label, single-arm, investigator-initiated phase II study is designed to evaluate combination treatment of nivolumab and TM5614, a plasminogen activator inhibitor (PAI-1) inhibitor as 3 or more line treatment in NSCLC patients who underwent standard treatment. The primary endpoint is the objective response rate and the secondary endpoints are progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety. Recruitment began in September 2023 and is expected to continue for approximately three years.
DISCUSSION
Currently, there is no standard 3 line treatment for advanced NSCLC, and we hope that the findings of this study will facilitate more effective treatments in this setting. Ethics and dissemination: the study protocol conformed to the ethical principles outlined in the Declaration of Helsinki. All patients will provide written informed consent prior to enrollment. Results will be published in a peer-reviewed publication.
TRIAL REGISTRATION
This study is registered to Japan Registry of Clinical Trials with number: jRCT2061230039 (19/July/2023).
PubMed: 38883673
DOI: 10.21037/jtd-23-1858 -
Journal of Thoracic Disease May 2024Little is known about the role of complement activation in acute pulmonary embolism (PE). We investigated whether complement activation is associated with the severity...
BACKGROUND
Little is known about the role of complement activation in acute pulmonary embolism (PE). We investigated whether complement activation is associated with the severity of acute PE, along with the associated prothrombotic state, systemic inflammation and neutrophil extracellular traps (NETs) formation.
METHODS
We studied 109 normotensive, non-cancer PE patients (aged 58.1±15.0 years). On admission prior to initiation of anticoagulation, plasma soluble complement components, i.e., C3a and sC5b-9, were measured with enzyme-linked immunosorbent assay (ELISA), along with thrombin generation, fibrinolysis proteins (plasminogen, antiplasmin, plasminogen activator inhibitor-1), factor VIII (FVIII) activity, and fibrin clot properties, including clot permeability (K, a measure of clot density) and clot lysis time (CLT). Moreover, we determined inflammatory markers and citrullinated histone H3, a specific marker of NETs formation.
RESULTS
Patients in the lower tertile of C3a (≤1.45 ng/mL, n=37) had lower simplified Pulmonary Embolism Severity Index (sPESI) values and were less likely to have right ventricular (RV) dysfunction compared to the remaining subjects. The former subgroup also had 13% lower FVIII activity, but not fibrinogen, interleukin-6, fibrinolysis proteins, and thrombin generation. Plasma C3a levels correlated inversely with K and positively with CLT indicating formation of denser and poorly lysable clots in subjects with elevated C3a. Despite a positive association between C3a and sC5b-9, the latter parameter was solely associated with higher FVIII, but not with other variables.
CONCLUSIONS
We showed that in acute PE enhanced complement activation characterizes patients with poorer short-term prognosis who display prothrombotic fibrin clot properties and elevated FVIII, which supports the involvement of complement proteins in acute thromboembolism.
PubMed: 38883666
DOI: 10.21037/jtd-24-171 -
Cureus May 2024The no-reflow phenomenon is defined as the failure to restore coronary flow demonstrated by the reduced or missing flow in angiography despite the patent artery. There...
The no-reflow phenomenon is defined as the failure to restore coronary flow demonstrated by the reduced or missing flow in angiography despite the patent artery. There are pharmacological strategies proposed and studied to manage the no-reflow phenomenon. The medication groups used are purine nucleoside (adenosine), calcium channel blockers (verapamil, nicardipine), beta 2 receptor agonists (adrenaline, nitroprusside), fibrinolytic agents (streptokinase, tissue plasminogen activators), glycoprotein IIb/IIIa inhibitors (abciximab, tirofiban). We present a case of a woman hospitalized in non-ST elevation myocardial infarction (NSTEMI) conditions. The patient underwent coronary angiography, in which a single vessel coronary artery disease (CAD); left anterior descending (LAD) stenosis of 90% was found. In this condition, the patient underwent percutaneous coronary intervention (PCI) of LAD. The no-reflow phenomenon occurred with thrombolysis in myocardial infarction (TIMI) flow grade of 0 during the procedure. As a consequence, the patient presented chest pain and important hypotension (BP of 70/45). Because of the hypotensive state of the patient, we decided to administer intracoronary (IC) adrenaline directly. In our case, we used adrenaline as a first-line treatment for the no-flow phenomenon due to the hypotensive state during the PCI procedure. Generally, we initially use IC nitrate or IC adenosine to resolve the phenomenon, and when the no-reflow persists we use IC adrenaline because of its side effects mentioned above. Anyway, we believe that in specific cases of hypotension and bradycardia, the use of adrenaline as the first line of therapy should be considered.
PubMed: 38883139
DOI: 10.7759/cureus.60338 -
Exploration of Hypertension Following Traumatic Renal Hematoma Formation and Page Kidney Discussion.Cureus May 2024Page kidney is defined as a rare cause of secondary hypertension due to a subcapsular hematoma externally compressing the kidney resulting in the activation of the...
Page kidney is defined as a rare cause of secondary hypertension due to a subcapsular hematoma externally compressing the kidney resulting in the activation of the renin-angiotensin-aldosterone system (RAAS). This phenomenon consists of numerous etiologies including acute or chronic traumatic or non-traumatic events. In this case, we report on an acute unilateral hematoma following blunt renal trauma as the result of a fall from standing height treated with tissue plasminogen activator (tPA) infusion and image-guided drainage. Qualities within this case and how they are paralleled in the diagnosis of a Page kidney are explored. A brief review of current etiologies and management plans per the literature review will also be discussed.
PubMed: 38883132
DOI: 10.7759/cureus.60468 -
Matrix Biology Plus Aug 2024Cardiac fibrosis is characterized by excessive accumulation and deposition of ECM proteins. Cardiac fibrosis is commonly implicated in a variety of cardiovascular...
Cardiac fibrosis is characterized by excessive accumulation and deposition of ECM proteins. Cardiac fibrosis is commonly implicated in a variety of cardiovascular diseases, including post-myocardial infarction (MI). We have previously developed a dual-delivery nanogel therapeutic to deliver tissue plasminogen activator (tPA) and Y-27632 (a ROCK inhibitor) to address MI-associated coronary artery occlusion and downregulate cell-contractility mediated fibrotic responses. Initial studies were conducted on glass substrates. The study presented here employs the use of polyacrylamide (PA) gels and microgel thin films to mimic healthy and fibrotic cardiac tissue mechanics. Soft and stiff polyacrylamide substrates or high and low loss tangent microgel thin films were utilized to examine the influence of cell-substrate interactions on dual-loaded nanogel therapeutic efficacy. In the presence of Y-27632 containing nanogels, a reduction of fibrotic marker expression was noted on traditional PA gels mimicking healthy and fibrotic cardiac tissue mechanics. These findings differed on more physiologically relevant microgel thin films, where early treatment with the ROCK inhibitor intensified the fibrotic related responses.
PubMed: 38882395
DOI: 10.1016/j.mbplus.2024.100150 -
Indian Heart Journal Jun 2024Left-sided mechanical prosthetic heart valve thrombosis (PVT) occurs because of suboptimal anticoagulation and is common in low-resource settings. Urgent surgery and...
BACKGROUND
Left-sided mechanical prosthetic heart valve thrombosis (PVT) occurs because of suboptimal anticoagulation and is common in low-resource settings. Urgent surgery and fibrinolytic therapy (FT) are the two treatment options available for this condition. Urgent surgery is a high-risk procedure but results in successful restoration of valve function more often and is the treatment of choice in developed countries. In low-resource countries, FT is used as the default treatment strategy, though it is associated with lower success rates and a higher rate of bleeding and embolic complications. There are no randomized trials comparing the two modalities.
METHODS
We performed a single center randomized controlled trial comparing urgent surgery (valve replacement or thrombectomy) with FT (low-dose, slow infusion tissue plasminogen activator, tPA) in patients with symptomatic left-sided PVT. The primary outcome was the occurrence of a complete clinical response, defined as discharge from hospital with completely restored valve function, in the absence of stroke, major bleeding or non-CNS systemic embolism. Outcome assessment was done by investigators blinded to treatment allocation. The principal safety outcome was the occurrence of a composite of in-hospital death, non-fatal stroke, non-fatal major bleed or non-CNS systemic embolism. Outcomes will be assessed both in the intention-to-treat, and in the as-treated population. We will also report outcomes at one year of follow-up. The trial has completed recruitment.
CONCLUSION
This is the first randomized trial to compare urgent surgery with FT for the treatment of left-sided PVT. The results will provide evidence to help clinicians make treatment choices for these patients. (Clinical trial registration: CTRI/2017/10/010159).
PubMed: 38879396
DOI: 10.1016/j.ihj.2024.06.013 -
Neurology Jul 2024
Topics: Humans; Cerebral Hemorrhage; Tissue Plasminogen Activator
PubMed: 38875509
DOI: 10.1212/WNL.0000000000209614 -
Turkish Neurosurgery Feb 2024Extraventricular drainage (EVD) combined with fibrinolytics may prove effective in reducing morbidity and mortality rates associated with intraventricular cerebral...
INTRODUCTION
Extraventricular drainage (EVD) combined with fibrinolytics may prove effective in reducing morbidity and mortality rates associated with intraventricular cerebral hemorrhage (IVH). This efficacy is primarily attributed to increased drainage capacity and a decreased risk of EVD obstruction when fibrinolytics are employed. This systematic review and meta-analysis aimed to determine the effectiveness of thrombolytics in this context.
METHODS
A literature review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (PROSPERO registration number: CRD42022332152). Articles were selected from various sources, including PubMed, Trip Database, LILACS, Cochrane Library, and ScienceDirect. Clinical trials focusing on IVH treatment using EVD and/or fibrinolytics were considered. The Risk of Bias in Non-randomized Studies of Interventions (ROB 2) tool was employed for bias assessment. A fixed-effects regression model was used following heterogeneity analysis. Treatment effectiveness was evaluated based on mortality outcomes.
RESULTS
A total of 531 patients from four studies were included. The use of fibrinolytics significantly decreased IVH mortality compared with a placebo. The odds ratio (OR) for recombinant tissue plasminogen activator (rtPA) or alteplase was 0.54 [0.36; 0.82]. For urokinase (UK), the OR was 0.21 [0.03; 1.54], rendering it statistically non-significant. The overall OR was 0.52 [0.35; 0.78], and the heterogeneity I2 was 0% (indicating low heterogeneity).
CONCLUSION
While EVD alone is a common approach for managing hydrocephalus, its effectiveness is limited by potential blockages and infections. Combining EVD with UK or rtPA demonstrated improved patient outcomes. rtPA stands out as a reliable and effective option, while limited data are available regarding UK\'s effectiveness in reducing IVH mortality.
PubMed: 38874256
DOI: 10.5137/1019-5149.JTN.45919-23.1 -
Journal of the American Heart... Jun 2024Pulmonary arterial hypertension (PAH) ultimately leads to right ventricular failure and premature death. The identification of circulating biomarkers with prognostic...
BACKGROUND
Pulmonary arterial hypertension (PAH) ultimately leads to right ventricular failure and premature death. The identification of circulating biomarkers with prognostic utility is considered a priority. As chronic inflammation is recognized as key pathogenic driver, we sought to identify inflammation-related circulating proteins that add incremental value to current risk stratification models for long-term survival in patients with PAH.
METHODS AND RESULTS
Plasma levels of 384 inflammatory proteins were measured with the proximity extension assay technology in patients with PAH (n=60) and controls with normal hemodynamics (n=28). Among these, 51 analytes were significantly overexpressed in the plasma of patients with PAH compared with controls. Cox proportional hazard analyses and C-statistics were performed to assess the prognostic value and the incremental prognostic value of differentially expressed proteins. A panel of 6 proteins (CRIM1 [cysteine rich transmembrane bone morphogenetic protein regulator 1], HGF [hepatocyte growth factor], FSTL3 [follistatin-like 3], PLAUR [plasminogen activator, urokinase receptor], CLSTN2 [calsyntenin 2], SPON1 [spondin 1]) were independently associated with death/lung transplantation at the time of PAH diagnosis after adjustment for the 2015 European Society of Cardiology/European Respiratory Society guidelines, the REVEAL (Registry to Evaluate Early and Long-Term PAH Disease Management) 2.0 risk scores, and the refined 4-strata risk assessment. CRIM1, PLAUR, FSTL3, and SPON1 showed incremental prognostic value on top of the predictive models. As determined by Western blot, FSTL3 and SPON1 were significantly upregulated in the right ventricle of patients with PAH and animal models (monocrotaline-injected and pulmonary artery banding-subjected rats).
CONCLUSIONS
In addition to revealing new actors likely involved in cardiopulmonary remodeling in PAH, our screening identified promising circulating biomarkers to improve risk prediction in PAH, which should be externally confirmed.
Topics: Humans; Male; Female; Biomarkers; Proteomics; Middle Aged; Prognosis; Pulmonary Arterial Hypertension; Adult; Animals; Risk Assessment; Case-Control Studies; Receptors, Urokinase Plasminogen Activator; Follistatin-Related Proteins; Disease Models, Animal; Predictive Value of Tests; Inflammation; Inflammation Mediators; Risk Factors; Bone Morphogenetic Protein Receptors, Type II; Pulmonary Artery
PubMed: 38874078
DOI: 10.1161/JAHA.123.032888