Hemorrhagic Events Research Articles

Clinical efficacy of intracavernous injection of platelet lysate for erectile dysfunction

BackgroundAmong the emerging treatments for erectile dysfunction (ED), platelet-rich plasma (PRP), known for its ability to enhance tissue repair and regeneration, stands out as a promising therapeutic approach. In this innovative study, we aimed to assess the efficacy of intracavernous injections of platelet lysate (PL), a derivative of PRP, in improving erectile function among ED patients.MethodsWe enrolled twenty-six patients, aged between 35 and 70 years (mean age 51.6 ± 11.3 years), who had been experiencing ED for over six months and had an International Index of Erectile Function-5 (IIEF-5) score of 21 or less. Participants received autologous PL injections intracavernously every two weeks for a total of five administrations. We assessed Erection Hardness Score (EHS) and International Index of Erectile Function-5 (IIEF-5) bi-weekly for 16 weeks and conducted penile Doppler ultrasounds pre- and post-treatment to record peak systolic velocity (PSV) and resistance index (RI).ResultsBefore treatment, the mean EHS was 2.15 ± 0.88 and IIEF-5 was 10.92 ± 5.28. Remarkable improvements were observed post-treatment, with the EHS significantly increasing to 3.15 ± 0.83 (p < 0.05) and IIEF-5 to 17.23 ± 5.26 (p < 0.05). Penile Doppler ultrasound exhibited an increase in both PSV and RI post-treatment, with the rise in RI being statistically significant.ConclusionsOur findings indicate that intracavernous injections of PL substantially enhance erectile function, as evidenced by improvements in EHS, IIEF-5, and the RI of penile Doppler ultrasound, without hemorrhagic events or other adverse reactions apart from temporary pain at the injection site during the 16-week follow-up period. These encouraging results suggest that PL injections are a safe and effective treatment modality for patients with moderate ED, potentially providing a less invasive and more physiologically friendly alternative to current ED management strategies.Trial registrationThe study received approval from the Institutional Review Board of National Taiwan University Hospital (IRB Number 202008061RIPC, date of registration 08/28/2020).

Risk of death, thromboembolic events, and bleeding in elderly patients with Atrial Fibrillation and Clinical Complexity who are not taking oral anticoagulation

Abstract Background Patients with Atrial Fibrillation (AF) often exhibit Clinical Complexity (CC), defined as ≥2 features, i.e. patients aged ≥75 years plus a body mass index (BMI) &amp;lt; 23/kg/m2 and/or bleeding history and/or chronic kidney disease. No data are available about the clinical course of patients with Atrial Fibrillation (AF) and CC who are not taking oral anticoagulation (OAC). Purpose To assess the risk of thrombotic and hemorrhagic events in patients with Atrial Fibrillation (AF) and CC who are not taking OAC. Methods Retrospective study with a health care research network (TriNetX). Based on the ICD-10-CM codes entered between 2011-2022 from 85 health care organizations mainly located in the United States, AF patients ≥75 years with CC were categorized into two groups based on the use of OAC during the last year before the study period. The primary outcomes were the one-year risk of death, major cardiovascular events ([MACE]: heart failure, stroke, and myocardial infarction), and major bleeding (central nervous system, gastrointestinal, internal bleeding, and hypovolemic shock). Secondary outcomes were each component of the primary outcome and catheter ablation. Cox regression analyses were used to calculate hazard ratios (HRs) and 95% CIs following propensity score matching 1:1. Results Overall, we identified 271,402 AF CC patients not on OAC (80.1±6.8 years, 46.5% females) and 87,101 AF CC patients on OAC (79.8±6.5 years, 47.6% females). Before PSM, AF CC patients not on OAC showed no significant differences in cardiovascular and bleeding risk factors but were less treated with pharmacological treatment than AF CC patients on OAC. After PSM, no significant differences were found between the two groups, but AF CC not on OAC were at higher risk of all-cause death (HR 1.54, 95%CI 1.50-1.57), MACE (HR 1.13, 95%CI 1.11-1.16), and major bleeding (HR 1.34, 95%CI 1.31-1.38), when compared to AF CC on OAC. AF CC patients not on OAC were associated with a higher risk of each component of the primary outcome and with a lower use of catheter ablation procedures (HR 0.48, 95%CI 0.43-0.54) (Table 1). The risk of the composite outcomes was the highest in those with all the three CC components. A progressive increase in OAC prescription was observed during the follow-up period, with increasing of NOACs and lower use of warfarin being observed. There was a clear temporal relationship between increasing OAC prescription and incidence of bleeding in CC patients (Figure 1) Conclusions AF CC patients not on OAC have a high risk of all-cause death, thrombotic and hemorrhagic events. Over time, increasing NOAC use was associated with more bleeding in CC patients. New antithrombotic approaches aimed at reducing thrombotic risk without increasing bleeding risk are needed in these patients.Figure 1 OAC new prescriptions

Predictors of Right vEntricular Failure aftER LVAD implantation: PREFER LVAD study

Abstract Introduction The use of left ventricular assist devices (LVAD) is increasing both as bridge-to-transplantation or destination therapy, considering the lack of heart donors for transplantation in advanced heart failure (AHF) population. Right ventricular post-implantation failure, major bleedings and infective events remain the principal adverse events in LVAD carriers, thus an accurate selection of candidates is needed. Purpose To identify between clinical, laboratory, standard and advanced (Speckle Tracking, STE) echocardiography, and right heart catheterization (RHC) indices, the best predictors of outcome after LVAD implantation. Materials and Methods We screened in our third-level center 30 patients with AHF, followed up from May 2013 to February 2022, for the assessment of LVAD implantation suitability. They all underwent a complete cardiological history collection, electrocardiography, standard and STE left ventricular (LV) and left atrial (LA) size and function assessment. Regarding the right ventricle, SIENA score parameters, including RV sphericity index, RV free wall longitudinal strain (LS), right ventricular fractional area change (RVFAC), and 3D ejection fraction were used for exclude RV disfunction. RHC was performed on the same day of echocardiography. Follow-up was conducted at 1, 3, 6, 9 and 12 months repeating all the assessments, for the occurrence of RV failure, all-causes mortality, hemorrhagic events and re-hospitalization for heart failure. With a univariate and multivariate statistical analysis, we went to test among all the parameters the possible predictors of outcome. Results The final population consists of 29 patients (93% male, mean age of 63±11 years), in NYHA class III or IV and a severe reduction of left ventricular (LV) ejection fraction (EF), in whom arterial hypertension and smoking, present or previous, were present in 58% and 65% of cases, respectively. The population was divided into two groups according to the occurrence of at least one cardiovascular event. 11 major events were recorded: including 4 hemorrhagic events, 3 all-causes mortality and 4 hospital admission for HF. No RV failure occurred in the first 12 months of follow-up. No differences were identified between the two groups in terms of echocardiographic indices and RV function, including RVFAC or RV-FWLS. At univariate analysis (see Table 1), the only parameter able to predict major CV events was central venous pressure (CVP)/pulmonary capillary wedge pressure (PCWP) ratio, obtained by RHC, an index of balance between right and left heart filling pressure. Conclusions A careful application of SIENA score indices before LVAD implantation can significantly reduce the incidence of post-operative RV failure, as in our small population. Our results also confirmed the paramount role of RHC in the diagnostic work up of AHF.

Impact of differences in body mass index, body surface area and lean body mass on clinical outcomes in patients with atrial fibrillation receiving edoxaban: 4-year follow-up data from ETNA-AF-Europe

Abstract Background In patients with atrial fibrillation (AF) treated with non-vitamin K antagonist oral anticoagulants, extremes in body weight and its anthropometric correlates (body mass index [BMI], body surface area [BSA] and lean body mass [LBM]) may affect drug exposure and the occurrence of thromboembolic or haemorrhagic events. Purpose To investigate the association of BMI, BSA and LBM with clinical outcomes according to sex in edoxaban-treated patients with AF using 4-year data from ETNA-AF-Europe (NCT02944019). Methods The prospective, observational ETNA-AF-Europe study followed patients with AF receiving edoxaban for up to 4 years. In this subanalysis, patients were categorised into tertiles (low, middle, and high) for BMI, BSA and LBM and stratified by sex. Baseline characteristics and rates of any thromboembolic and haemorrhagic events per 100 patient-years ([%]/100PY) are reported using 4-year follow-up data. Results Of 13,164 patients, 7461 were men and 5703 were women. Table 1 shows the ranges of BMI, BSA and LBM, defining the low, middle, and high tertiles, and their corresponding baseline characteristics. Irrespective of sex, patients in the low tertile for BMI, BSA and LBM were older and more likely to have renal impairment, history of stroke, and to receive appropriate edoxaban 30mg or non-appropriate edoxaban 60mg. Patients in the high tertile were more likely to have diabetes and hypertension. Overall, the rate (%)/100PY of any thromboembolic event was slightly lower (0.8 vs 1.1%), whereas the corresponding rate of any haemorrhagic event was slightly higher (1.9 vs 1.7%) in men vs women (Figure 1). For BMI, BSA and LBM in men, rates (%)/100PY of any thromboembolic event were similar among tertiles (low, middle, high; BMI, 0.9, 0.8 and 0.8%; BSA, 0.9, 0.8 and 0.8%; LBM, 0.9, 0.7 and 0.9%). For BMI, rates (%)/100PY of any haemorrhagic event were similar among tertiles in men (BMI, 1.9, 1.8 and 2.0%), but highest in the low tertile for BSA and LBM (BSA, 2.4, 1.8 and 1.5%; LBM, 2.4, 1.8 and 1.5%). In women, rates (%)/100PY of any thromboembolic event were similar for all tertiles of BMI but were highest in the low tertile for BSA and LBM (low, middle, high; BMI, 1.3, 1.1 and 1.1%; BSA, 1.4, 1.1 and 1.0%; LBM, 1.4, 1.2 and 0.9%; Figure 1). For BMI, BSA and LBM, rates (%)/100PY of any haemorrhagic event were highest in the low tertile in women (low, middle, high; BMI, 2.1, 1.6 and 1.6%; BSA, 2.2, 1.7 and 1.4%; LBM, 2.3, 1.5 and 1.5%). Conclusions At the 4-year follow-up in this real-life registry, low rates (%/100PY) of any thromboembolic event ([0.7–1.4%]) were observed regardless of patients' BMI, BSA, LBM, or sex. However, higher rates of any haemorrhagic events were observed in the low ([2.2–2.4%]) vs middle ([1.5–1.8%]) and high ([1.4–1.5%]) tertiles for BSA and LBM, suggesting that these variables, more than BMI, should be considered when analysing outcomes in patients with AF treated with edoxaban.Baseline characteristicsFigure 1

Respective impact of bleeding and ischemic complications of mortality after percutaneous coronary interventions: substudy from the FRANCE-PCI registry

Abstract Background Patients undergoing percutaneous coronary interventions (PCI) remain at high risk of both bleeding and ischemic events, both burdened with high morbimortality. The respective impact of both type of complications in contemporary PCI, however, remains unclear. Purpose To evaluate and compare the respective impact of ischemic and bleeding complications on mortality after PCI Methods The FRANCE PCI is an ongoing registry of consecutive French patients undergoing PCI and monitored for one year thereafter. Patients presenting with complications after the index PCI were categorized as ischemic complications in case of stent thrombosis, myocardial infarction, stroke or unplanned revascularization, as hemorrhagic complications in case of bleeding BARC ≥3 or as ischemic and hemorrhagic when both types of events occurred in the same patients. The impact of ischemic and hemorrhagic complications on mortality was evaluated separately for the index hospitalization and the 12-months follow-up after hospital discharge, using multivariate logistic model and Cox proportional hazards model, respectively. The multivariate Cox model was developed using complications as time-dependent variables and estimating the hazard ratios (HRs) over 3 periods of time (0 to 8 weeks, 8 to 24 weeks, and 24 to 52 weeks). Consequently, the proportional hazard assumption, tested using the Schoenfeld test, was met for each period. Multiple imputations were performed for missing data on covariates. Results A total of 54,599 patients, with a median age of 69 [60.0-78.0] years, 75.0% male, underwent PCI in 30 centers between 2014 and 2020, in an elective setting for 47% of the cases. During the index hospitalization, an ischemic and hemorrhagic complications occurred in 610 (1.1% 95%CI 1.0-1.2) and 531 (1.0% 95%CI 0.9-1.1) patients, respectively, while the mortality rate was 2.1% 95%CI 2.0-2.2. The association between ischemic, hemorrhagic and ischemic and hemorrhagic events with mortality was aOR 8.4 95%CI 6.4-10.9, aOR 10.3 95%CI 8.1-13.2 and aOR 13.2 95%CI 7.0-24.7, respectively. Among the 51,738 patients alive and not lost-to-follow-up after discharge, an ischemic and hemorrhagic complications occurred in 2,727 (5.3% 95%CI 5.1-5.5) and 1,022 (2.0% 95%CI 1.9-2.1) patients, respectively, while the mortality incidence was 3.8% 95%CI 3.6-4.0. The associations between ischemic, hemorrhagic and ischemic and hemorrhagic events with mortality according to the periods of time are detailed in Table 1 and Figure 1. Conclusion Both ischemic and hemorrhagic complications after PCI are associated with increased risk of mortality. The risk is particularly increased during the early period after the index PCI and diminishes over time, albeit faster after ischemic complications alone, compared to hemorrhagic events alone or the association of ischemic and hemorrhagic complications.

Association of ticagrelor vs clopidogrel with net adverse clinical events in NSTEMI patients with mild thrombocytopenia

Abstract Backgrounds: Guidelines currently recommend aspirin plus ticagrelor as the preferred dual antiplatelet therapy (ADPT) for non-ST-elevation myocardial infarction (NSTEMI). However, there are no established recommendations for managing NSTEMI patients with mild thrombocytopenia, defined as a platelet count of 100~150×109/L. Purpose This study aims to investigate the association between ticagrelor and clopidogrel with ischemic and hemorrhagic events in NSTEMI patients with a platelet count of 100~150×109/L. Methods A retrospective cohort study was conducted using data from the Health and Medical Big Data Super Platform from January 2010 to June 2023. The study included NSTEMI patients with a platelet count of 100~150×109/L who received DAPT consisting of aspirin and a P2Y12 receptor antagonist (eithor clopidogrel or ticagrelor). Patients were followed up for at least one year. The inverse probability of treatment weighting (IPTW) approach based on propensity score was used to balance the observed confounders between treatments. The primary endpoint was net adverse events (NACE) at 1 year, composed of ischemic events (recurrent myocardial infarction or ischemic stroke), Bleeding Academic Research Consortium (BARC) classification ≥ 3, and cardiac death. Secondary outcomes included cardiac death, recurrent myocardial infarction and, ischemic stroke. Results The study cohort comprised 2969 participants, with a median age of 72 years and 29.2.0% female. After adjustment using inverse probability of treatment weighting, ticagrelor and clopidogrel showed similar rates of NACE (aHR, 0.84; 95%Cl, 0.58-1.21). Cardiac death (aHR, 0.99; 95%Cl, 0.54-1.83) and ischemic stroke (aHR, 0.94; 95%Cl, 0.49-1.81) did not significantly differ between the two groups. However, ticagrelor was associated with a lower rate of recurrent myocardial infarction (aHR, 0.44; 95%Cl, 0.21-0.93). Conclusion In routine clinical practice, among NSTEMI patients with a platelet count of 100~150×109/L, ticagrelor, did not showed a significant difference in the risk of NACE at 1 year compared with clopidogrel. However, ticagrelor was associated with a lower rate of recurrent myocardial infarction. Further research is warranted to confirm the this conclusion.

Risk of thromboembolic and haemorrhagic events associated with anticoagulation among 11,355 patients with non-valvular atrial fibrillation and thrombocytopenia

Abstract Background Oral anticoagulation (OAC) is the mainstay for stroke prophylaxis in patients with non-valvular atrial fibrillation (NVAF). Management is challenging among patients with NVAF complicated with thrombocytopenia. Purpose We compared risk of thromboembolic and hemorrhagic events between vitamin-k antagonist (VKA) and direct oral anticoagulants (DOAC) users. Methods We retrospectively analyzed patients with thrombocytopenia and NVAF prescribed VKA (N=5,251, 46.2%) and DOAC (N=6,104, 53.8%) between January 2012 and July 2022 in 16 public hospitals in Hong Kong. Mild to moderate thrombocytopenia was defined as mean platelet count (PLT) 100-150 × 10^9/L and 50-100 × 10^9/L respectively, during the year of OAC initiation. Propensity-matched cohorts of VKA and DOAC were generated on the basis of age, sex, baseline co-morbidities (components of CHA2DS2VASC and HAS-BLED scores) and medications. Time to intracranial hemorrhage (ICH), gastrointestinal bleeding (GIB) and ischemic stroke (IS) was analyzed using competing risk regression, accounting for death as competing risk. Subgroup analysis was performed to detect heterogeneity of effect across mild and moderate thrombocytopenia. Secondary outcome included (i) comparisons between 4 DOAC agents with full dose; (ii) Full-dose DOAC vs. reduced-dose DOAC. Results Of the whole cohort (N=11,355, mean age 75.8±10.5, female 38.6%), 10.3% (n=1,174) and 89.7% (n=10,181) had moderate and mild thrombocytopenia, respectively. After propensity-score matching, VKA and DOAC (n=4,302 each cohort) users were well balanced at baseline characteristics, with a median follow-up of 4.0 (IQR: 1.6-7.3) years. Overall, utilization of DOAC was associated with reduced risk of ICH [Hazards Ratio (HR) 0.56 (95% CI 0.45-0.70)] and GIB [HR 0.60 (95% CI 0.48-0.75)], compared with VKA. No difference in risk of IS was observed [HR 1.00 (95%CI 0.83-1.20)]. Dosing reduction of DOAC made no difference in all outcomes. Subgroup analysis demonstrated the benefit in decreasing GIB might be more marked in moderate thrombocytopenia [(HR 0.24 (95%CI 0.09-0.61)], than in mild thrombocytopenia [HR 0.64 (95%CI 0.51-0.81)]. Conclusion In patients with NVAF and thrombocytopenia, DOAC has similar efficacy but better safety profile than VKA. In terms of GIB, the superiority appeared to be more pronounced in patients with more significant thrombocytopenia.

Drug interactions in incident NOACs users and risk of bleeding

Abstract Introduction Oral anticoagulants (NOACs) are known to have a better safety profile than Vitamin K antagonists, but their metabolism largely depends on the P-glycoprotein and CYP3A4. All drugs inhibiting those proteins may affect NOACs’ bioavailability, by increasing the risk of drug interactions, particularly the risk of bleeding. Purpose The objective was to describe the pattern of polypharmacy in a large cohort of NOAC users, at baseline and within one year after starting anticoagulant treatment. Materials and Methods All persons residing in the catchment areas of Caserta LHU during the years 2012–2020 were considered. From the source population, all patients with at least 1 year of database history and receiving at least one NOAC dispensing during the observation period were identified. Of these, incident (i.e. no NOAC dispensing within one year prior to the first dispensing date, Index Date) NOAC users were included into the cohort and represented the majority of the patients enrolled (97,4%). The comparison of the distribution of interacting drugs number dispensed Pre-ID (within three months before the Index date) and Post-ID (within 12 months after Index date) was explored stratified by high/low dose of anticoagulant. 20.491 incident NOAC users were identified from Caserta LHU and 16,367 (79.9%) NOAC incident users with at least one year of follow-up after ID were included in the analysis. NVAF was the main indication for use of the study cohort (64.3%) and almost 60% of incident NOAC users treated for NVAF received high-dose NOAC. The frequency of incident NOAC users with at least one hospitalization for major bleeding within one year after ID was calculated and stratified by high/low dose of NOACs and the number of drug interactions. A statistically significant test result was considered if p ≤ 0.05. Results The number of interacting drugs dispensed within one year after ID increased from pre-ID to post-ID. 2,077 (12.7%) incident NOAC users without any interacting drugs within 3 months pre-ID received 1 interacting drug within one year after ID. 11.3% and 8.4% of incident NOAC users increased from 1 interacting drug (Pre-ID) to 2 interacting drugs (Post-ID) and from 2 interacting drugs (Pre-ID) to 3-5 interacting drugs (Post-ID) (Table 1). The proportion of NOAC users with a major bleeding increased with the increasing number of interacting drugs, reaching 2.9% and 2.1% among low-dose and high-dose NOAC users with more than 9 interacting drugs (Table 2). Conclusions The results of the current analysis suggest that independently from the type and the dose of NOAC, the number of interacting drugs prescribed with NOACs tends to increase after the first administration of NOACs. Hemorrhagic events are more related to the number of interacting drugs instead of dose of anticoagulant.Table 1 Table 2

Prevention of mechanical valve thrombosis with a combination of the factor Xa inhibitor edoxaban plus aspirin in swine: intermediate results from the EdoValves project

Abstract Background Patients with an implanted mechanical heart valve (MHV) currently have a contraindication to the use of non-vitamin K antagonist oral anticoagulants (NOACs) based on the unfavorable results of the RE-ALIGN trial with dabigatran. We hypothesized that the combination of a Factor Xa inhibitor, acting upstream of thrombin generation, plus aspirin, may effectively prevent valve thrombosis, providing a much more friendly and viable alternative to vitamin K antagonists for such patients. We tested this in a swine model with a recently implanted mechanical valve prosthesis in the mitral position, combining the most unfavorable conditions promoting mechanical valve thrombosis, based on (a) the implanting position; (b) recent surgery; (c) the high thrombogenicity of the animal model. The study was approved by the Animal Ethics Committee of the University of Pisa and the Italian Ministry of Health and conducted according to Good Clinical Practices for Animal Experiments. Methods 17 farm male pigs, weighing ≈30 kg at the beginning, underwent cardiac surgery under general anesthesia and with extracorporeal circulation to receive a 25 mm or 27 mm bileaflet Corcym Bicarbon mechanical heart valve replacement in the mitral position. Pigs were given 1 mg/kg enoxaparin immediately after surgery and started with the oral daily administration of edoxaban 1 mg/kg (30 mg, then escalated to 60 mg with the animal growth) + aspirin 100 mg, both given as crushed tablets with a food pellet since the animal awakening from anesthesia. An initially planned warfarin control group was quickly abandoned because of the extreme difficulty of controlling warfarin activity. Animals were submitted to blood sampling and transthoracic echocardiography at least twice in the follow-up when uneventful for up to three months or in case of health deterioration. The autopsy was performed by a certified pathologist after each spontaneous death or procured sacrifice. Results (Figure 1): Excluding 5 peri-operative deaths, 12 animals survived surgery. Of those, 6 died within the second month: pulmonary edema occurred in 3 cases, due to prosthesis-mismatch in the growing animals; pulmonary infection occurred in 1 subject; heart failure due to valve thrombosis occurred in 2 cases. Six swine were full-term survivors in good health status up to the 3-month planned observational time. No hemorrhagic events were ever documented. Conclusion The combination of edoxaban + aspirin effectively avoided valve thrombosis events in 10 out of 12 (83%) analyzable animals and was safe from bleeding complications. The study is ongoing up to a predicted sample size of ≥20 animals. If further confirmed, these data may open the possibility of an alternative to vitamin K antagonists in humans with the fixed-dose drug combination here used, without the need for continuous anticoagulation monitoring and with expected greater safety.Figure 1

Association of ticagrelor vs clopidogrel with net adverse clinical events in STEMI patients with mild thrombocytopenia

Abstract Backgrounds Current guidelines advocate for aspirin plus ticagrelor as the preferred dual antiplatelet therapy (DAPT) for ST-elevation myocardial infarction (STEMI). However, there is a lack of consensus or guidelines to direct clinicians on managing STEMI patients with mild thrombocytopenia, defined as a platelet count of 100~150×109/L. Purpose This study aims to investigate the association between ticagrelor and clopidogrel with ischemic and hemorrhagic events in STEMI patients with a platelet count of 100~150×109/L. Methods A retrospective cohort study was conducted using Health and Medical Big Data Super Platform from January 2010 to June 2023.The study included STEMI-patients with a platelet count of 100~150×109/L who received DAPT consisting of aspirin and a P2Y12 receptor antagonist (either clopidogrel or ticagrelor) All STEMI patients with a platelet count of 100~150×109/L were included in the analysis with a follow-up of at least one year. The inverse probability of treatment weighting (IPTW) approach based on propensity score was utilized to balance observed confounders between treatments. The primary endpoint was net adverse events (NACE) at 1 year, including ischemic events (recurrent myocardial infarction or ischemic stroke), Bleeding Academic Research Consortium (BARC) classification ≥ 3, and cardiac death. Secondary outcomes were cardiac death, recurrent myocardial infarction, and ischaemic stroke. Results The study cohort consisted 2941 participants with median age of 69 years, and 21.0% were female. Following adjustment using the inverse probability of treatment weighting, ticagrelor and clopidogrel demonstrated similar NACE (aHR, 0.86; 95%CI, 0.60-1.23). Cardiac death (aHR, 0.69; 95%CI, 0.36-1.31), recurrent myocardial infarction (aHR, 0.94; 95%CI, 0.50-1.78), and ischaemic stroke (aHR, 0.62; 95%CI, 0.34-1.14) did not significantly differ between the two groups. Conclusion In routine clinical practice, among STEMI patients with a platelet count of 100~150×109/L ticagrelor compared with clopidogrel, was not associated with a significant difference in the risk of NACE at 1 year. Further research is warranted to assess whether ticagrelor is more effective than clopidogrel in this particular patient population.

Association of ticagrelor vs clopidogrel with net adverse clinical events in patients with mild thrombocytopenia undergoing PCI

Abstract Backgrounds Current guidelines recommend aspirin plus ticagrelor as the preferred dual antiplatelet therapy (DAPT) for managing ST-elevation myocardial infarction (STEMI). However, there is a lack of consensus or guidelines to direct clinicians on managing patients with mild thrombocytopenia, defined as a platelet count of 100~150×109/L, undergoing percutaneous coronary intervention (PCI). Purpose This study aims to investigate the association between ticagrelor and clopidogrel with ischemic and hemorrhagic events for patients with mild thrombocytopenia undergoing PCI. Methods A retrospective cohort study of patients with mild thrombocytopenia undergoing PCI who received DAPT consisting of aspirin and a P2Y12 receptor antagonist (includinig clopidogrel or ticagrelor) was conducted using Health and Medical Big Data Super Platform from January 2010 to June 2023. All patients meeting the criteria were included in the analysis, with a follow-up of at least one year. Propensity Score Matching (PSM) was performed to equalize the effects of following characteristics: age, sex, hypertension, diabetes, dyslipidemia, stroke, atrial fibrillation, Killip class, percutaneous coronary intervention (PCI), beta-blockers, statins, calcium channel blockers (CCB), angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (ACEI or ARB), angiotensin receptor-neprilysin inhibitor (ARNI), diuretic, organic nitrates, and oral anticoagulation. The primary endpoint was net adverse clinical events (NACE) at 1 year, composed of ischemic events (recurrent myocardial infarction or ischemic stroke), Bleeding Academic Research Consortium (BARC) classification ≥ 3, and cardiac death. Secondary outcomes included the components of NACE. Results A total of 3647 patients met the inclusion criteria, with 2684 receiving aspirin plus clopidogrel and 963 receiving aspirin plus ticagrelor, matched by a 1:3 ratio using the PSM method. Demographic characteristics were well balanced between the clopidogrel and ticagrelor groups. The 1-year risk of NACE did not significantly differ between ticagrelor and clopidogrel (11.1% vs. 8.4%, p=0.370). Similarly, there was no significant difference in the risk of cardiac death (7.3% vs. 4.2%, p=0.720), recurrent myocardial infarction (9.3% vs. 5.8%, p=0.550), ischemic stroke (8.8% vs. 6.7%, p=0.055), or BARC type ≥ 3 bleeding (7.9% vs. 4.5%, p=0.990). Conclusion In routine clinical practice, among patients with a platelet count of 100~150×109/L undergoing PCI, ticagrelor compared with clopidogrel was not associated with a significant difference in the risk of NACE at 1 year. Further research is warranted to assess whether ticagrelor is more effective than clopidogrel in this setting, considering potential unmeasured confounders.

Outcomes and management of Haemoptysis in the Fontan population

Abstract Background Patients with a Fontan circulation for palliation of a univentricular congenital heart defect commonly possess pulmonary vascular abnormalities including arteriovenous malformations (AVM), aortopulmonary and venous-venous collaterals (1). These vessels are prone to haemorrhage which may result in life-threatening haemoptysis (2). This risk is increased with oral anticoagulant medication, given to reduce the risk of thromboembolism in Fontan patients (3). Management of these patients is difficult, and strategies vary across institutions. Purpose We aim to describe our experience with managing adult Fontan patients presenting with haemoptysis in a tertiary centre with a large Fontan cohort. Methods We retrospectively reviewed the records of 410 adult Fontan patients. Individuals admitted to our institution with an episode of haemoptysis were included. Details relating to anticoagulation regimens, interventions and mortality of patients were captured. Results From a cohort of 410 Fontan patients, 35 haemorrhagic events were observed in 11 patients (2.68%). The median age at initial haemoptysis was 24.5 years (range 19 to 43 years). 6 of the 11 patients were female (54.5%). Haemoptysis recurred in 8 of the 11 patients (72.7%). 2 out of 11 had a prior history of haemoptysis in childhood. All patients were administered with oral vitamin K antagonists at presentation. 24 of the 35 events were managed conservatively with IV fluids, anticoagulation reversal and tranexamic acid (66.7%). 11 events required catheter-based interventions, with coil and/or plug embolization of bleeding vessels. Prior to intervention, CT successfully identified potential bleeding sites in 10 of the 11 events (90.9%) but could not visualise all vessels that were subsequently embolized. The most common culprits for haemoptysis were aortopulmonary collaterals, followed by AVMs and venous-venous collaterals. In severe cases, more extensive management was required including transfusions, bronchoscopy, intubation, surgical exploration (1 patient) and pneumonectomy (1 patient). 3 patients died following recurrent severe haemoptysis (27.3%), and 2 patients died of subsequent Fontan failure and sudden cardiac death respectively. Total mortality of the cohort is 5 out of 11 (45.5%) with a median follow up of 10.75 years (range 3 days to 27 years). Conclusions Haemoptysis is a rare but potentially fatal complication in patients who have undergone a Fontan procedure. The variability in presentation of this condition mandates an individualised approach to management with involvement of a multidisciplinary team. There is a high rate of recurrence following haemoptysis and a comprehensive assessment of all potential bleeding sites is necessary. CT is a useful tool to help facilitate this and guide further management. Our policy is to close all potential sources of bleeding as CT and invasive angiography rarely identifies an active point of bleeding.

A phase 1 study of the amino acid modulator pegcrisantaspase and venetoclax in relapsed or refractory acute myeloid leukemia

Glutamine dependency has been shown to be a metabolic vulnerability in acute myeloid leukemia (AML). Prior studies using several in vivo AML models showed that depletion of plasma glutamine induced by the long-acting crisantaspase (pegcrisantaspase or PegC) was synergistic with the BCL-2 inhibitor venetoclax (Ven), resulting in significantly reduced leukemia burden and enhanced survival. Here, we report a phase 1 study (NCT04666649) of Ven and PegC combination (VenPegC) for treating adult patients with relapsed or refractory AML, including patients who had previously received Ven. The primary endpoints were incidence of regimen limiting toxicities (RLT) and maximum tolerated dose (MTD). Twenty-five patients received at least one PegC dose with Ven and 18 efficacy-evaluable patients completed at least one VenPegC cycle; 12 (67%) had previously received Ven. Hyperbilirubinemia was the RLT and occurred in 60% of patients treated with VenPegC; 20% had Grade ≥3 bilirubin elevations. MTD was determined to be Ven 400 mg daily with biweekly PegC 750 IU/m2. The most common treatment-related adverse events of any Grade in 25 patients who received VenPegC included antithrombin III decrease (52%), elevated transaminases (36-48%), fatigue (28%), and hypofibrinogenemia (24%). No thromboembolic or hemorrhagic adverse events or clinical pancreatitis were observed. The overall complete remission rate in efficacy-evaluable patients was 33%. Response correlated with alterations in proteins involved in mRNA translation. In patients with RUNX1 mutations, the composite complete rate was 100%.

Factors affecting the collateral ingrowth from the superficial temporal artery after Encephalo-Duro-Arterio-Synangiosis in adult patients with Moyamoya disease

BackgroundMultiple factors have been proposed to affect the vessel ingrowth from the superficial temporal artery (STA) after Encephalo-Duro-Arterio-Synangiosis (EDAS). MethodsThis retrospective single-center analyses included patients with Moyamoya Disease (MMD) undergoing EDAS from January 1st, 2013, to December 31st, 2023. Evaluated variables included demographic characteristics, clinical presentation, technical details, modified Rankin Scale (mRS) scores, and radiographic outcomes. Univariate and multivariate analysis was performed to identify factors favoring the ingrowth of collaterals from the STA. ResultsForty adult patients with MMD, most commonly females (77.5 %) with a median age of 48, underwent 56 EDAS. The most common initial presentations were ischemic events (75.0 %), followed by hemorrhagic events (27.5 %) and seizures (7.5 %). Digital angiography performed at a median of 13.7 months post-procedure revealed collateral growth from the STA in 78.6 % of cases, with a Matsushima grade A identified in 35.7 % of the revascularized hemispheres. Univariate analysis showed more collaterals in patients with a larger preoperative STA diameter (p=0.035), higher Suzuki grades (p=0.021) and longer angiographic follow-ups (p=0.048). Patients with occlusion of the internal carotid artery (ICA; p<0.01), middle cerebral artery (MCA; p<0.01), or anterior cerebral artery (ACA; p<0.01) also had more collateral ingrowth. Multivariate analysis revealed that ICA occlusion (OR=6.54; 95 % CI=1.03–41.48) and ACA occlusion (OR=6.52; 95 % CI=1.02–41.67) as predictors of collateral ingrowth from the STA. ConclusionICA and ACA occlusion were associated with success after EDAS. Longer follow-ups and larger STA demonstrated significant association on univariate analysis, but lost significance after adjusting for other procedural characteristics.

Noninvasive optical monitoring of cerebral hemodynamics in a preclinical model of neonatal intraventricular hemorrhage.

Intraventricular hemorrhage (IVH) is a common complication in premature infants and is associated with white matter injury and long-term neurodevelopmental disabilities. Standard diagnostic tools such as cranial ultrasound and MRI are widely used in both preclinical drug development and clinical practice to detect IVH. However, these methods only provide endpoint assessments of blood accumulation and lack real-time information about dynamic changes in ventricular blood flow. This limitation could potentially result in missed opportunities to advance drug candidates that may have protective effects against IVH. In this pilot study, we aimed to develop a noninvasive optical approach using diffuse correlation spectroscopy (DCS) to monitor real-time hemodynamic changes associated with hemorrhagic and sub-hemorrhagic events in a preclinical rabbit model of IVH. DCS measurements were conducted during the experimental induction of IVH, and results were compared with ultrasound and histological analysis to validate findings. Significant changes in hemodynamics were detected in all animals subjected to IVH-inducing procedures, including those that did not show clear positive results on ultrasound. The study revealed progressively elevated coefficients of variation in blood flow, particularly driven by increased oscillations within the 0.05-0.1 Hz frequency band. These hemodynamic changes were more pronounced in animals that developed IVH, as confirmed by ultrasound. Our findings suggest that real-time optical monitoring with DCS can provide critical insights into pathological blood flow changes, offering a more sensitive and informative tool for evaluating potential therapeutics in the context of IVH.

Risk factors for intracerebral hemorrhage by five specific bleeding sites: Japan Public Health Center-based Prospective Study.

Evaluating the risk factors for intracerebral hemorrhage is indispensable for primary prevention. However, the pathogenesis varies depending on the bleeding site, and few prospective studies have explored risk factors in detail for each site. The Japan Public Health Center-based Prospective Study is a prospective study comprising a population-based sample of Japanese adults in 1990 (Cohort I) and in 1993 (Cohort II). A total of 34,137 participants (11,907 men and 22,230 women) were enrolled in this study and followed up until 2009 for Cohort I and until 2012 for Cohort II. The association between risk factors (age, sex, blood pressure, serum cholesterol, triglycerides, blood glucose, body mass index, smoking, and drinking status) and intracerebral hemorrhage by its bleeding site (lobes, putamen, thalamus, cerebellum, and brainstem) was assessed using Cox proportional hazards analysis. During a median 20-year follow-up, 571 intracerebral hemorrhage events occurred. Hypertension was associated with an increased risk of total intracerebral hemorrhage, but not lobar hemorrhage. The multivariable hazard ratio (95% confidence intervals) was 2.09 (1.75-2.50) for total intracerebral hemorrhage. In contrast, a low serum total cholesterol level was associated only with lobar hemorrhage (1.73 (1.01-2.96)). Heavy drinking was associated with the risk of total and putamen hemorrhage, and obesity was associated with the risk of putamen hemorrhage. The present study identified different risk factors depending on the bleeding site of intracerebral hemorrhage.

Technical Approaches for Coil Embolization of Unruptured Small Anterior Choroidal Artery Aneurysms: A Focus on Anatomical Flow Preservation of the Anterior Choroidal Artery.

The anterior choroidal artery (AChA) supplies the corticospinal tract related to the motor function of the upper and lower limbs. Aneurysms arising at the AChA are not common and exhibit various patterns of involvement of the AChA. Hence, managing an AChA aneurysm poses a high risk of neurological deficits. We report technical issues related to the outcome of coil embolization for unruptured AChA aneurysms. We obtained Institutional Review Board approval for this study. In the past 2 years, 18 consecutive patients (6 males and 12 females, aged 32-68) with unruptured AChA aneurysms were treated using embolization. We present technical details, pre- and post-procedural patient statuses, angiographic outcomes, and recurrence during a mean follow-up period of 12 months (range 3-25). The patients with AChA (n=18) underwent stent-assisted coiling (n=14), coiling (n=2), or stenting only (n=2). The technical strategy for aneurysm embolization included a low-lying approach into the aneurysm, stent-strut abutting (protecting) coil framing to block inflow and avoid compromising AChA flow, and direct intra-aneurysmal angiography via a microcatheter. Angiographic results showed complete occlusion (n=11), neck remnant (n=5), and sac remnant (n=2). During the follow-up, there were 2 recurrences, and 1 of them required a re-procedure. All patients showed no change in clinical status (modified Rankin scale score=0) and did not experience any ischemic or hemorrhagic events during the follow-up period. AChA aneurysms can be managed through embolization using various techniques. Such technical concepts may enhance the safety and improve the outcomes of AChA aneurysm embolization.

Rare Co-occurrence of Spinal Cord Hemorrhage from Radiation-induced Cavernous Hemangioma and Classical Hodgkin Lymphoma Post-transplant Lymphoproliferative Disorder.

Post-transplant lymphoproliferative disorders (PTLDs) are lymphoproliferative diseases that occur after solid organ transplantation or hematopoietic stem cell transplantation (HSCT). The development of PTLD is often associated with reactivation of Epstein-Barr virus (EBV). A 26-year-old woman with a history of HSCT and total-body irradiation developed spinal cord hemorrhage from a radiation-induced cavernous hemangioma (RICH) shortly after the development of classical Hodgkin lymphoma PTLD with EBV reactivation. Although little is known about the factors leading to hemorrhagic events from spinal cord RICH, we suspect that EBV reactivation may have been a factor contributing to the hemorrhage in the present case.

Dual Antiplatelet Versus Alteplase for Early Neurologic Deterioration in Minor Stroke With Versus Without Large Vessel Occlusion: Prespecified Post Hoc Analysis of the ARAMIS Trial.

Dual antiplatelet therapy (DAPT) was noninferior to alteplase in minor nondisabling strokes in the ARAMIS trial (Antiplatelet Versus R-tPA for Acute Mild Ischemic Stroke); however, early neurological deterioration (END) associated with vessel stenosis may benefit from DAPT. We investigated whether the efficacy of DAPT was greater than alteplase in minor strokes with no large vessel occlusion (LVO). This study was a prespecified post hoc analysis of the ARAMIS trial and included patients with responsible vessel examination in the as-treated analysis set of the ARAMIS trial who were divided into LVO group and non-LVO group. In each group, patients were further classified into DAPT and intravenous alteplase treatments. Primary outcome was END at 24 hours defined as more than or equal to 4-point National Institutes of Health Stroke Scale score increase compared with baseline, and safety outcomes were symptomatic intracerebral hemorrhage and bleeding events during study. The primary analysis was estimated with a risk difference calculated by a generalized linear model including adjusted different baseline characteristics between treatments. Of 723 patients from the ARAMIS trial, 480 patients were included: 36 were categorized into LVO group and 444 into non-LVO group, of whom 20 patients had END. Compared with intravenous alteplase, a lower proportion of END was found after DAPT treatment in the non-LVO group (adjusted risk difference, -4.8% [95% CI, -6.9% to -2.6%]; P<0.001), but not in the LVO group (adjusted risk difference, 2.3% [95% CI, -17.6% to 22.3%]; P=0.82). The interaction was marginally significant between groups (P=0.06). In the non-LVO group, a lower proportion of bleeding events was found after DAPT treatment than intravenous alteplase (adjusted risk difference, -6.4% [95% CI, -8.9% to -3.9%]; P<0.001). Other safety outcomes were similar between the 2 treatments. Among minor nondisabling acute ischemic stroke without LVO, DAPT may be superior to intravenous alteplase regarding preventing END with a better safety profile. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03661411.

USO DE ANTICOAGULANTES EM PACIENTES COM FIBRILAÇÃO ATRIAL: UMA REVISÃO SISTEMÁTICA

Atrial fibrillation (AF) is one of the most prevalent cardiac arrhythmias, associated with a high risk of thromboembolic complications such as stroke. The use of anticoagulants is essential to prevent these events, with warfarin being widely used for many years. However, new oral anticoagulants (NOACs), such as apixaban and rivaroxaban, have emerged as saferand more effective alternatives, especially in vulnerable subgroups like patients with chronickidney disease and the elderly. This study reviews recent literature on the use of anticoagulants in AF patients, comparing NOACs with warfarin in terms of efficacy, safety,and adherence. Nine studies were selected from PubMed and ScienceDirect databases. Theresults indicate that NOACs have a better safety profile concerning hemorrhagic events and are easier to use due to the lack of frequent monitoring requirements. However, warfarin is still widely used, especially in lower-income countries, due to its more accessible cost. It is concluded that while NOACs represent a significant advancement in AF management, their widespread implementation depends on financial accessibility and the individual suitability ofeach patient.