Search

Results from multiple electrode aggregometry (MEA) may vary according to pre-analytic factors. This study aimed to analyze the association of time from blood draw to MEA in patients undergoing percutaneous coronary intervention (PCI). In this observational single-center cohort study, platelet aggregation (aggregation units, U) was quantified by MEA (Multiplate Analyzer) after stimulation with adenosine diphosphate (ADP; final concentration [Fc] 6.4 μM), thrombin receptor activating peptide (TRAP; Fc 32 μM), or arachidonic acid (AA; Fc 0.5 mM) in patients treated with ASA and clopidogrel following PCI. High on-clopidogrel platelet reactivity (HPR) was defined as ADP-induced platelet aggregation ≥ 46 U. The manufacturer recommends performing the analysis within 30–180 min after blood draw. Patients were grouped according to the time from blood draw to MEA: 30–180 min, 180 min. Platelet function of 273 patients with coronary artery disease undergoing PCI with dual antiplatelet therapy was analyzed. The median age was 72 years (interquartile range, IQR 62–79) and 179 (66%) were male. Median ADP-, TRAP-, and AA-induced aggregation was 25 (IQR 18–36) U, 79 (IQR 63–96) U, and 12 (IQR 7–18) U, respectively. For those analyzed within 30–180 min from blood draw, no significant correlation of time from blood draw to MEA was observed 1) ADP (r = − 0.04, p = 0.51); 2) TRAP (r = − 0.06, p = 0.32); 3) AA (r = − 0.03, p = 0.67). In patients undergoing percutaneous coronary intervention and treated with dual antiplatelet therapy, the time from blood draw to multiple electrode aggregometry does not correlate with ADP- induced aggregation when the measurement occurred within the recommended time interval of 30–180 min after blood draw.

Introduction Patients with atrial fibrillation (AF) after percutaneous coronary intervention (PCI) receive clopidogrel and direct oral anticoagulation. Platelet inhibition by clopidogrel varies according to CYP2C19 genotype. This study aimed to investigate the association of CYP2C19 genotype with antiplatelet effect of clopidogrel and ischemic and bleeding risk. Methods In this prospective observational study, patients with AF after PCI were grouped according to CYP2C19*2 and *17 diplotypes: *2/non-17* or *2/*2 as reduced metabolizers (RM), non-*2/*17 or *17/*17 as increased metabolizers (IM), and the remaining as normal metabolizers (NM). Platelet aggregation [U] was quantified by multiple electrode aggregometry. The primary outcome was time to death, myocardial infarction, or stroke (MACE) at 6 months. The secondary outcome was time to non-major clinically relevant (NMCR) or major bleedings. Results 156 patients were enrolled between May 2020 and May 2021. The median age was 78 years (interquartile range, IQR 71–82) and 109 (70%) were male. 31 patients (20%) were RM, 74 patients (47%) NM and 51 patients (33%) IM. The median ADP-induced platelet aggregation was not significantly different across these groups (RM: 12.8 [U]; NM: vs. 12.8 [U]; IM: 11.7 [U]; P = 0.39).The primary outcome occurred in 11 (7%) patients (RM: 1 [3%]; NM: 7 [9%]; IM 3[6%]). The secondary outcome occured in 3 RM (10%) and in 20 (16%) with NM + IM subtypes (HR 0.65 [95% CI 0.19–2.18], P = 0.485). Conclusion In this analysis reduced metabolizers were not at excessively increased risk of MACE. A trend for less bleeding was observed in carriers of loss-of-function allele CYP2C19*2.

Background Antiphospholipid antibodies and other coagulation markers are associated with ischemic risk in patients with coronary artery disease without oral anticoagulation (OAC). Aim To assess the association of antiphospholipid antibodies (aPL) and conventional markers of coagulation with ischemic and bleeding risk in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI). Patients and methods In this prospective single center observational cohort study, patients with AF and an indication for OAC were enrolled after PCI. Dilute Russell's viper venom time (DRVVT) was used to determine lupus anticoagulants (LA) in direct OAC-free plasma. Anti-cardiolipin IgG (aCL), IgM and anti-beta2GP-1-IgG (aβ2GP1) were analyzed by enzyme linked immunosorbent assay (ELISA). Fibrinogen C (FIBC), d-dimers and prothrombin fragments 1 and 2 (PF1+2) were measured in citrated plasma. Immature platelet fraction (IPF [%]) and absolute (IPF abs. [103/μl]) were measured in EDTA-blood. The primary ischemic outcome was defined as time to major adverse cardiovascular events (MACE: all-cause death, myocardial infarction, or stroke) assessed at 6 months. Bleeding was defined according to the International Society of Thrombosis and Haemostasis (ISTH) and the Bleeding Academic Research Consortium (BARC). Results 158 patients were enrolled between May 2020 and May 2021. The median age was 78 years (interquartile range, IQR 72–82), 111 (70%) were male, and 39 (25%) presented with acute coronary syndrome. All Patients were treated with clopidogrel and OAC, 145 (92%) in addition with acetylsalicylic acid (ASA). 32 patients (20%) had ≥1 antiphospholipid antibody (aPL; LA: 19 [12%], aCL: 14 [9%], aβ2GP1: 2 [1%]). D-dimers were elevated in 74 patients (47%), FIBC was increased in 40 (25%) and PF1+2 in 68 patients (43%). IPF [%] was elevated in 28 (18%) and IPF abs. [103/μl] in 11 (7%). The presence of aPL was neither significantly associated with MACE, nor with bleeding risk. Elevated d-dimers were significantly associated with higher risk for MACE (HR=5.1, 95% CI [1.1; 23.4], p=0.04), major ISTH bleeding events (HR= 6.9, 95% CI [1.5; 30.8], p=0.01) and BARC bleeding type 3 or 5 (HR=6.4, 95% CI [1.4; 28.7], p=0.02). Increased levels of FIBC were associated with risk of MACE (HR= 3.6, 95% CI [1.1; 12.0], p=0.03 (Table 1). Conclusion In patients with AF undergoing PCI, high levels of d-dimers and fibrinogen C indicate an increased ischemic risk. Elevated d-dimers are associated with higher risk for bleeding. aPL positivity was not significantly associated with outcome possibly due to low sample size. A combined panel of biomarkers might be suitable to assess ischemic and bleeding risk in patients with AF following PCI. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Faculty of Medicine, Freiburg

Extracorporeal membrane oxygenation (ECMO) is used for patients with cardiopulmonary failure and is associated with severe bleeding and poor outcome. Platelet dysfunction may be a contributing factor. The aim of this prospective observational study was to characterize platelet dysfunction and its relation to outcome in ECMO patients. Blood was sampled from thirty ECMO patients at three timepoints. Expression of CD62P, CD63, activated GPIIb/IIIa, GPVI, GPIbα and formation platelet-leukocyte aggregates (PLA) were analyzed at rest and in response to stimulation. Delta granule storage-pool deficiency and secretion defects were also investigated. Fifteen healthy volunteers and ten patients with coronary artery disease served as controls. Results were also compared between survivors and non-survivors. Compared to controls, expression of platelet surface markers, delta granule secretion and formation of PLA was reduced, particularly in response to stimulation. Baseline CD63 expression was higher and activated GPIIb/IIIa expression in response to stimulation was lower in non-survivors on day 1 of ECMO. Logistic regression analysis revealed that these markers were associated with mortality. In conclusion, platelets from ECMO patients are severely dysfunctional predisposing patients to bleeding complications and poor outcome. Platelet dysfunction on day 1 of ECMO detected by the platelet surface markers CD63 and activated GPIIb/IIIa is associated with mortality. CD63 and activated GPIIb/IIIa may therefore serve as novel prognostic biomarkers, but future studies are required to determine their true potential. Supplementary Information The online version contains supplementary material available at 10.1007/s11239-021-02562-9.

Background: Work-related musculoskeletal disorders (WRMSDs) are a public concern to social-care and health systems, as well as individuals. Globally, WRMSDs are classified as one of the prevalent causes of disability. Objectives: The primary objective of this study was to determine work-related risk associated with musculoskeletal disorders amongst flower farm workers. The secondary objective was to determine the relationship between WRMSD risk over the previous 12 months and socio-demographic characteristics. Method: A cross-sectional descriptive study was conducted. A sample of 270 participants was drawn from 897 farm workers, of which 184 presented with WRMSD as assessed using the Nordic Musculoskeletal Questionnaire. Quantitative data were collected using the Rapid Entire Body Assessment questionnaire. Inferential statistics were analyzed using the Pearson's chi-squared test (X2) test and based on an alpha level of p< 0.05. Descriptive statistics were presented using frequencies and percentages. Results: Respondents who reported medium risk were 49 (26.6%), 80 (43.5%) reported high risk while 55 (29.9%) reported very high risk. There was no relationship between WRMSD risk and socio-demographic characteristics. Conclusions: Flower farm workers in Kenya were found to be at risk of sustaining WRMSDs although socio-demographic factors did not play a role in the level of risk. Clinical Implications: The high prevalence of WRMSDs necessitates policy reform in the flower farm industry. Furthermore, the timely identification of potential disorders and the associated risk factors is necessary to ensure early intervention. KEY WORDS: Work-related risk, Work-related musculoskeletal disorders, Farm workers.

Background We performed a trial to evaluate the efficacy of a blended intervention with personalized health coaching and virtual cardiac rehabilitation to improve medication adherence and risk factors. The trial was terminated early. Here, we describe findings from a root cause analysis and lessons learned. Methods SmartGUIDE was an open-label, single-center trial that randomized participants with coronary artery disease who were prescribed a statin and/or P2Y12 inhibitor 1:1 to either usual care or the added use of a mobile app with components of cardiac rehabilitation paired with personal virtual coaching. The primary outcome was medication adherence: proportion of days covered (PDC). The planned sample size was 132. We performed a root cause analysis to evaluate processes from study development to closure. Results During trial conduct, the technology start-up withdrew the intervention. The study was terminated early with 63 participants randomized and data from 26 available for analysis. The median PDC was high in both groups (intervention group 94%, interquartile range [IQR] 88%–96%; control group: 99%, IQR 95%–100%). Root cause analysis identified factors for not achieving trial objectives: key factors that limited enrollment (inclusion criteria, low penetration of compatible smartphones), participant retention or engagement (poor app product, insufficient technology support), and suboptimal choice of a technology partner (technology start-up's inexperience in health care, poor product design, inadequate fundraising). Conclusion We identified important and preventable factors leading to trial failure. These factors may be common across digital health trials and may explain prior observations that many such trials are never completed. Careful vetting of technology partners and more pragmatic study designs may prevent these missteps.

Background: High on-clopidogrel platelet reactivity (HPR) following percutaneous coronary intervention (PCI) is associated with increased ischemic risk. It is unclear whether conventional definitions of HPR apply to patients with concomitant oral anticoagulation (OAC). This study aimed to compare the performance of multiple platelet aggregometry (MEA) and thrombelastography (TEG) to detect HPR in patients with atrial fibrillation (AF) and indication for an OAC. Methods: In this observational single-center cohort study, MEA and TEG were performed in patients with AF with an indication for OAC on day 1 to 3 after PCI. The primary outcome was HPR as assessed by MEA (ADP area under the curve ≥ 46 units [U]) or TEG (MAADP ≥ 47 mm), respectively. The secondary exploratory outcomes were a composite of all-cause death, myocardial infarction (MI) or stroke and bleeding, as defined by the International Society on Thrombosis and Hemostasis, at 6 months. Results: Platelet function of 39 patients was analyzed. The median age was 78 (interquartile range [IQR] was 72–82) years. 25 (64%) patients were male, and 19 (49%) presented with acute coronary syndrome. All patients received acetylsalicylic acid and clopidogrel prior to PCI. Median (IQR) ADP-induced aggregation, MAADP, TRAP-induced aggregation, and MAthrombin were 9 (6–15) U, 50 (43–60) mm, 54 (35–77) U and 65 (60–67) mm, respectively. The rate of HPR was significantly higher if assessed by TEG compared with MEA (25 [64%] vs. 1 [3%]; p < 0.001). Within 6 months, four (10%) deaths, one (3%) MI and nine (23%) bleeding events occurred. Conclusion: In patients with AF undergoing PCI, the rates of HPR detected by TEG were significantly higher compared with MEA. Conventional cut-off values for HPR as proposed by consensus documents may need to be re-evaluated for this population at high ischemic and bleeding risk. Further studies are needed to assess the association with outcomes.

COVID-19 is a viral prothrombotic respiratory infection. Heparins exert antithrombotic and anti-inflammatory effects, and might have antiviral properties. We aimed to investigate whether thromboprophylaxis with enoxaparin would prevent untoward hospitalisation and death in symptomatic, but clinically stable outpatients with COVID-19.OVID was a randomised, open-label, parallel-group, investigator-initiated, phase 3 trial and was done at eight centres in Switzerland and Germany. Outpatients aged 50 years or older with acute COVID-19 were eligible if they presented with respiratory symptoms or body temperature higher than 37·5°C. Eligible participants underwent block-stratified randomisation (by age group 50-70 vs70 years and by study centre) in a 1:1 ratio to receive either subcutaneous enoxaparin 40 mg once daily for 14 days versus standard of care (no thromboprophylaxis). The primary outcome was a composite of any untoward hospitalisation and all-cause death within 30 days of randomisation. Analysis of the efficacy outcomes was done in the intention-to-treat population. The primary safety outcome was major bleeding. The study was registered in ClinicalTrials.gov (NCT04400799) and has been completed.At the predefined formal interim analysis for efficacy (50% of total study population), the independent Data Safety Monitoring Board recommended early termination of the trial on the basis of predefined statistical criteria having considered the very low probability of showing superiority of thromboprophylaxis with enoxaparin for the primary outcome under the initial study design assumptions. Between Aug 15, 2020, and Jan 14, 2022, from 3319 participants prescreened, 472 were included in the intention-to-treat population and randomly assigned to receive enoxaparin (n=234) or standard of care (n=238). The median age was 57 years (IQR 53-62) and 217 (46%) were women. The 30-day risk of the primary outcome was similar in participants allocated to receive enoxaparin and in controls (8 [3%] of 234 vs 8 [3%] of 238; adjusted relative risk 0·98; 95% CI 0·37-2·56; p=0·96). All hospitalisations were related to COVID-19. No deaths were reported during the study. No major bleeding events were recorded. Eight serious adverse events were recorded in the enoxaparin group versus nine in the control group.These findings suggest thromboprophylaxis with enoxaparin does not reduce early hospitalisations and deaths among outpatients with symptomatic COVID-19. Futility of the treatment under the initial study design assumptions could not be conclusively assessed owing to under-representation of older patients and consequent low event rates.SNSF (National Research Programme COVID-19 NRP78: 198352), University Hospital Zurich, University of Zurich, Dr-Ing Georg Pollert (Berlin), Johanna Dürmüller-Bol Foundation.

In den letzten Jahren finden strukturelle kardiale Interventionen zunehmend Anwendung in der klinischen Routine. Trotz der raschen Einfuhrung und Weiterentwicklung dieser Techniken, ist die Evidenz fur die optimale antithrombotische Therapie nach solchen Interventionen limitiert, da randomisierte Studien zum Vergleich verschiedener antithrombotischer Therapien fur die meisten Einsatzgebiete fehlen. Diese Empfehlung fasst den gegenwartigen Erkenntnisstand zusammen. Basierend auf den zur Verfugung stehenden Daten, werden Behandlungsempfehlungen formuliert, die Arzten und ihren Patienten die Entscheidungsfindung erleichtern sollen.

ZUSAMMENFASSUNGDieser Artikel soll einen Überblick über klinische Studien des Jahres 2019 zur antithrombotischen Therapie kardiovaskulärer Erkrankungen geben. Im Jahr 2019 wurden auf den jährlichen Hauptkongressen der 3 international führenden kardiovaskulären Gesellschaften (American College of Cardiology, European Society of Cardiology und American Heart Association) 15 Studien zur antithrombotischen Therapie kardiovaskulärer Erkrankungen vorgestellt und in einer der führenden Fachzeitschriften veröffentlicht. Der Trend geht zu einer personalisierten antithrombotischen Therapie. Während eine verkürzte Dauer der Thrombozytenaggregationshemmung nach perkutaner Koronarintervention eher sicher erscheint, profitieren Patienten mit hohem individuellem ischämischen Risiko möglicherweise von einer verlängerten intensivierten antithrombotischen Therapie. Die Standardtherapie für Patienten mit Vorhofflimmern nach perkutaner Koronarintervention besteht aus einem Nicht-Vitamin-K-Antagonist oralen Antikoagulanz und einem P2Y12-Inhibitor. Nach 12 Monaten ohne neues Ereignis reicht bei den meisten dieser Patienten eine orale Antikoagulation ohne zusätzliche Thrombozytenaggregationshemmung aus. Nach Katheter-gestütztem Aortenklappenersatz kann für Patienten ohne Indikation für eine orale Antikoagulation eine Therapie mit 10 mg Rivaroxaban nicht empfohlen werden.

Background Timely acquisition of 12-lead Electrocardiogram (ECG) in the emergency department (ED) is crucial and recommended by current guidelines. Objectives To evaluate the association of medical history of coronary artery disease (hCAD) on door-to-ECG time in the ED. Methods In this single center, retrospective cohort study, patients admitted to ED for cardiac evaluation were grouped according to hCAD and no hCAD. The primary outcome was door-to-ECG time. A multivariate analysis adjusted for the cofounders sex, age, type of referral and shift was performed to evaluate the association of hCAD with door-to-ECG time. Results 1101 patients were included in this analysis. 362 patients (33%) had hCAD. Patients with hCAD had shorter door-to-ECG time (20 min. [Inter Quartile Range [IQR] 13–30] vs. 22 min. [IQR 14–37]; p p = 0.007; 95% confidence Interval [CI] − 5.16 to − 0.84 min]). Conclusion In this single center registry, hCAD was associated with shorter door-to-ECG time. In patients presenting in ED for cardiac evaluation, timely ECG diagnostic should be facilitated irrespective of hCAD.

The purpose of this study is to investigate the role of platelet bone morphogenetic proteins (BMP)-4 during vascular inflammation and remodeling in a mouse model of carotid wire injury. Transgenic mice with a platelet-specific deletion of BMP-4 (BMP4Plt−/−) were generated. Intravital microscopy was performed to evaluate leukocyte adhesion to the vessel wall. Expression of adhesion molecules and chemokines were analyzed. Platelet-leukocyte aggregates (PLAs) were evaluated using flow cytometry. For carotid wire injury, BMP4Plt−/− mice were further crossed with LDLr−/− mice (BMP4Plt−/−/LDLr−/−) and fed with a high cholesterol diet for 2-weeks. Carotid wire injury was performed, and re-endothelialization and neointimal formation were evaluated. In comparison to the control mice, stimulation with TNFα resulted in fewer rolling and adherent leukocytes to the vessel wall in the BMP4Plt−/− mice. mRNA and protein expression of P-selectin and adhesion molecules were reduced in the aorta of the BMP4Plt−/− mice. In platelets from the BMP4Plt−/− mice, the expression of P-selectin was reduced, and fewer PLA formations were measured than in the control mice. Loss of platelet BMP-4 further prevented neointima formation after carotid wire injury. Endothelial regeneration after injury was decelerated in the BMP4Plt−/− mice, and confirmed in-vitro, where the deletion of platelet BMP-4 inhibited endothelial cell proliferation and migration. We demonstrate for the first time that platelet BMP-4 is involved during vascular inflammation and remodeling. This is partially mediated by the inhibition of platelet activation, reduced expression of adhesion molecules and inflammatory responses. Our findings identify platelet BMP-4 as a mediator of vascular inflammation in early atherosclerosis and restenosis.

Among the >120 modified ribonucleosides in the prokaryotic epitranscriptome, many tRNA modifications are critical to bacterial survival, which makes their synthetic enzymes ideal targets for antibiotic development. Here we performed a structure-based design of inhibitors of tRNA-(N1G37) methyltransferase, TrmD, which is an essential enzyme in many bacterial pathogens. On the basis of crystal structures of TrmDs from Pseudomonas aeruginosa and Mycobacterium tuberculosis, we synthesized a series of thienopyrimidinone derivatives with nanomolar potency against TrmD in vitro and discovered a novel active site conformational change triggered by inhibitor binding. This tyrosine-flipping mechanism is uniquely found in P. aeruginosa TrmD and renders the enzyme inaccessible to the cofactor S-adenosyl-l-methionine (SAM) and probably to the substrate tRNA. Biophysical and biochemical structure-activity relationship studies provided insights into the mechanisms underlying the potency of thienopyrimidinones as TrmD inhibitors, with several derivatives found to be active against Gram-positive and mycobacterial pathogens. These results lay a foundation for further development of TrmD inhibitors as antimicrobial agents. Ministry of Education (MOE) National Research Foundation (NRF) Published version This research was supported by the National Research Foundation of Singapore through the Singapore-MIT-Alliance for Research and Technology (SMART) Infectious Disease and Antimicrobial Resistance Interdisciplinary Research Groups; SMART Innovation Centre grant ING137070-BIO to P.C.D., L.C.F., and J.L.; and AcRF grants Tier1 RG154/14 and MOE2015- T2-2-075 to J.L.

Background The intravenous, rapidly acting P2Y12 inhibitor cangrelor reduces the rate of ischemic events during PCI with no significant increase in severe bleeding. However, the efficacy and safety of cangrelor compared with clopidogrel in patients treated with single vessel (SV)-percutaneous coronary intervention (PCI) or multivessel (MV)-PCI remains unexplored. Methods We studied the modified intention-to-treat population of patients from the CHAMPION PHOENIX trial who were randomized to either cangrelor or clopidogrel. We used logistic regression and propensity score matching to evaluate the effect of cangrelor compared with clopidogrel on the primary efficacy outcome (composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis) at 48 hours. The safety outcome was moderate or severe Global Utilization of Streptokinase and tPA for Occluded Arteries bleeding at 48 hours. Hypothesis Cangrelor is as efficacious and safe as clopidogrel in both SV and MV PCI. Results Among 10 854 patients, 9204 (85%) underwent SV- and 1650 (15%) MV-PCI. After adjustment, cangrelor was associated with similar reductions vs clopidogrel in the primary efficacy outcome in patients undergoing SV-PCI (4.5% vs 5.2%; odds ratio [OR] 0.81 [0.66-0.98]) or MV-PCI (6.1% vs 9.8%, OR 0.59 [0.41-0.85]; Pint 0.14). Similar results were observed after propensity score matching (SV-PCI: 5.5% vs 5.9%, OR 0.93 [0.74-1.18]; MV-PCI: 6.2% vs 8.9%, OR 0.67 [0.44-1.01]; Pint 0.17). There was no evidence of heterogeneity in the treatment effect of cangrelor compared with clopidogrel for the safety outcome. Conclusions In patients undergoing SV- or MV-PCI, cangrelor was associated with similar relative risk reductions in ischemic complications and no increased risk of significant bleeding compared with clopidogrel, which highlights the expanding repertoire of options for use in complex PCI.

Background: Direct oral anticoagulants (DOACs) have strict dosing guidelines, but recent studies indicate that inappropriate dosing is common, particularly in chronic kidney disease (CKD), for which it has been reported to be as high as 43%. Since 2011, the Veterans Health Administration (VA) has implemented anticoagulation management programs for DOACs, generally led by pharmacists, which has previously been shown to improve medication adherence. Objective: We investigated the prevalence of overdosing and underdosing of DOACs in the VA. Methods: Using data from the TREAT-AF cohort study (The Retrospective Evaluation and Assessment of Therapies in AF), we identified VA patients with newly diagnosed atrial fibrillation (AF) and receipt of a DOAC between 2003 and 2015. We classified dosing as correct, overdosed, or underdosed based on the Food and Drug Administration–approved dosing criteria. Results: Of 230 762 patients, 5060 received dabigatran (77.3%) or rivaroxaban (22.7%) within 90 days of AF diagnosis (age 69 [10[ years; CHA2DS2-VASc 1.6 [1.4]), of which 1312 (25.9%) had CKD based on estimated glomerular filtration rate Conclusion: Compared to recent studies of commercial payers and health-care systems, incorrect dosing of DOACs is less common across the VA. Pharmacist-led DOAC management or similar anticoagulation management interventions may reduce the risk of incorrect dosing across health-care systems.

IMPORTANCE: Patients with peripheral artery disease (PAD) are at high risk for myocardial infarction (MI). OBJECTIVE: To characterize the incidence and types of MI in a PAD population, identify factors associated with MI, and determine the association of MI with cardiovascular mortality and acute limb ischemia. DESIGN, SETTING, AND PARTICIPANTS: The Study Comparing Cardiovascular Effects of Ticagrelor and Clopidogrel in Patients With Peripheral Artery Disease (EUCLID) was a double-blind randomized clinical trial conducted at 811 sites in 28 countries that randomized 13 885 patients with symptomatic PAD to monotherapy with ticagrelor or clopidogrel. Participants had an ankle-brachial index (ABI) of 0.80 or less or previous lower extremity revascularization. Median follow-up was 30 months. For these analyses, patients were evaluated for MI occurrence during follow-up irrespective of treatment. Data were analyzed from June 2017 to September 2018. MAIN OUTCOMES AND MEASURES: An adjudication clinical events committee classified MI as type 1 (spontaneous), type 2 (secondary), type 3 (sudden cardiac death), type 4a (less than 48 hours after percutaneous coronary intervention), type 4b (definite stent thrombosis), or type 5 (less than 72 hours after coronary artery bypass graft). A multivariate regression model was developed by stepwise selection to identify factors associated with MI, and a time-dependent multivariate Cox regression analysis was performed to determine the association of MI with cardiovascular death and acute limb ischemia requiring hospitalization. RESULTS: Of the 13 885 patients included in this analysis, 9997 (72.0%) were male, and the median (interquartile range) age was 66 (60-73) years. Myocardial infarction occurred in 683 patients (4.9%; 2.4 events per 100 patient-years) during a median follow-up of 30 months. Patients experiencing MI were older (median [interquartile range] age, 69 [62-75] vs 66 [60-72] years), more likely to have diabetes (349 of 683 [51.1%] vs 4996 of 13 202 [37.8%]) or a previous lower extremity revascularization (466 of 683 [68.2%] vs 7409 of 13 202 [56.1%]), and had a lower ABI (if included by ABI) compared with censored patients. Of the 683 patients with MI during follow-up, the most common MI type was type 1 (405 [59.3%]), followed by type 2 (236 [34.6%]), type 4a (14 [2.0%]), type 3 (12 [1.8%]), type 4b (11 [1.6%]), and type 5 (5 [0.7%]). Postrandomization MI was independently associated with cardiovascular death (adjusted hazard ratio, 9.0; 95% CI, 7.3-11.2; P

Introduction and aim Current emergency treatment options for severe aortic valve stenosis include surgical aortic valve replacement (SAVR), transcatheter aortic valve replacement (TAVR) and balloon valvuloplasty (BV). So far no larger patient population has been evaluated regarding clinical characteristics and outcomes. Therefore we aimed to describe the use and outcome of the three therapy options in a broad registry study. Method and results Using German nationwide electronic health records, we evaluated emergency admissions of symptomatic patients with severe aortic valve stenosis between 2014 and 2017. Patients were grouped according to SAVR, TAVR or BV only treatments. Primary outcome was in-hospital mortality. Secondary outcomes were stroke, acute kidney injury, periprocedural pacemaker implantation, delirium and prolonged mechanical ventilation >48 hours. Stepwise multivariable logistic regression analyses including baseline characteristics were performed to assess outcome risks. 8,651 patients with emergency admission for severe aortic valve stenosis were identified. The median age was 79 years and comorbidities included NYHA classes III-IV (52%), coronary artery disease (50%), atrial fibrillation (41%) and diabetes mellitus (33%). Overall in-hospital mortality was 6.2% during a mean length of stay of 22±15 days. TAVR was the most common treatment (6,357 [73.5%]), followed by SAVR (1,557 [18%]) and BV (737 8.5%]). Patients who were treated with TAVR or BV were significantly older than patients with SAVR (mean age 81.3±6.5 and 81.2±6.9 versus 67.2±11.0 years, p Compared with BV only, SAVR patients (adjusted odds ratio [aOR] 0.25; 95% confidence interval [CI] 0.14–0.46; p Conclusion In-hospital mortality for emergency patients with symptomatic severe aortic valve stenosis is high. Our results showed that BV only therapy was associated with highest mortality, which is in line with current research. Yet, there is a trend towards more TAVR interventions and this study might imply that balloon valvuloplasty alone is insufficient. The role of BV as a bridging strategy to TAVR or SAVR needs to be further investigated. Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): Heart Center Freiburg University, Department of Cardiology and Angiology I, Faculty of Medicine, University of Freiburg, Freiburg, Germany

Background Bone morphogenic proteins (BMPs) are members of the TGFβ superfamily. They have distinct functions during hemostasis and play a central role in various pathologic conditions, including cardiovascular diseases. Recent findings demonstrate that BMPs are also expressed in platelets. However, their function is poorly understood. Here, we investigate the role of platelet BMP4 during vascular inflammation and vascular remodelling. Methods BMP4 floxed mice were crossed with PF4 Cre mice to generate platelet-specific deletion of BMP4 (BMP4Plt−/−). Intravital microscopy of mesenteric veins was performed to evaluate leukocyte adhesion upon stimulation with TNFα. Expression of adhesion molecules and chemokines were analysed by RT-PCR and Western Blot. P-selectin and platelet-leukocyte aggregates were evaluated using flow cytometry. For carotid wire injury, BMP4Plt−/− were further crossed with LDLr−/− mice (BMP4Plt−/−/LDLr−/−). At 8 weeks of age, BMP4Plt−/−/LDLr−/− mice and control littermates received a 2-week diet containing 15.8% wt/wt fat and 1.25% cholesterol. Carotid wire injury was performed at the age of 10 weeks. Re-endothelialisation and neointimal hyperplasia were evaluated. Results Platelet morphology and function did not differ between BMP4Plt−/− and control mice. Stimulation with TNFα resulted in increased rolling and adherence of leukocytes to the vessel wall which was reduced in BMP4Plt−/− mice (175±25 versus 50±7 rolling cells and 16±3 versus 7±2 adherent cells, respectively). Expression of P-selectin, adhesion molecules and the chemokines RANTES and PF-4 were reduced in BMP4Plt−/− mice. Platelet activation by thrombin was reduced in BMP4Plt−/− mice, resulting in diminished P-Selectin and JONA expression. Furthermore, monocyte infiltration and circulating leukocyte-platelet complexes were reduced in BMP4Plt−/− mice. Loss of platelet BMP4 prevented neointima formation after carotid wire injury (4.2x104±0.9x104μm2 versus 14.9x104±2.2x104μm2 in BMP4Plt−/−/LDLr−/− and control mice, respectively). Interestingly, endothelial regeneration after injury was decelerated in BMP4Plt−/− mice. This is further demonstrated in-vitro, where platelet BMP4 promoted endothelial cell proliferation and migration. Conclusion Platelet-BMP4 deficiency reduced vascular inflammation and ameliorated intima hyperplasia after wire injury. This is partly mediated by inhibition of platelet activation, reduced expression of adhesion molecules and inflammatory response. Our finding suggests that BMP4 is a promising target for the treatment of vascular inflammation and restenosis. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Else-Kröner Fresenius Foundation; German Cardiac Society

Background: There is limited data evaluating the prescription practices for antithrombotic therapy in patients with atrial fibrillation (AF) following elective percutaneous coronary intervention (PCI).Objective: This single-center, single-operator, retrospective cohort study aimed to evaluate trends of antithrombotic treatment strategies in patients with AF undergoing elective PCI.Methods: Patients with AF who electively underwent PCI performed by a single interventionalist between April 2013 and May 2018 were identified. The primary outcome was the antithrombotic therapy at discharge assessed by chart review: triple (TAT, triple antithrombotic therapy) or dual (DAT, dual antithrombotic therapy) antithrombotic therapy and vitamin K antagonist (VKA) or non-vitamin K antagonist oral anticoagulant (NOAC), respectively.Results: Of 6,135 screened patients, 259 met the inclusion criteria. Among these, 133 (51%) patients received NOAC- and 126 (49%) VKA-therapy. Compared with patients on NOAC therapy, patients treated with VKA had higher bleeding risk (mean HAS-BLED-Score; 2.3 vs. 2.0; p = 0.02) and more co-morbidities (estimated glomerular filtration rate

Background: Activated platelets release serotonin during acute myocardial infarction (AMI), aggravating myocardial damage and ischemia/reperfusion (I/R) injury. However, serum serotonin and its potential role as a biomarker for myocardial infarction and I/R injury have not been studied so far. Methods: In this investigator-initiated pilot study, we examined 38 patients with ST-segment myocardial infarction (STEMI). We determined serum serotonin levels prior to percutaneous coronary intervention and 8, 16, and 24 h afterwards. We studied whether serum serotonin was associated with I/R injury assessed by ECG analysis and by analysis of TIMI myocardial perfusion grade (TMP) and myocardial blush grade (MGB). Serum serotonin levels were compared to an age-matched control group consisting of patients admitted to the emergency department for any other reason than STEMI. Results: Serum serotonin levels were not elevated in the myocardial infarction group compared to the control cohort and they did not show any timeline kinetics after STEMI. They were not associated with the severity of coronary artery disease, the outcome of coronary angiography, the extent of I/R injury, or the degree of heart failure. Conclusions: Serum serotonin is not suitable as a biomarker after myocardial infarction and in the assessment of I/R injury.

OBJECTIVENeurosurgery occupies a prominent place in medical malpractice, but cases are still underreported in Brazil. This study describes the socioeconomic issues of medical malpractice in neurosurgery procedures and how they culminate in unfavorable outcomes in a developing country.METHODSThe authors analyzed 112 neurosurgical procedures listed in the Brazilian Hospital Information System (Sistema de Informações Hospitalares do Sistema Único de Saúde [SIHSUS]) records in the DATASUS (Departamento de Informática do SUS) database between January 2008 and February 2020. Malpractice data were collected using the JusBrasil platform, with the authors searching the name of each of the 112 neurosurgical procedures plus “medical malpractice” among the jurisprudence records for January 2008 to February 2020. A simple linear regression analysis was performed using appropriate software. Analyses were considered statistically significant at p < 0.05.RESULTSAccording to DATASUS, 842,041 neurosurgical procedures were performed by the Brazilian Unified Health System between January 2008 and February 2020. The mean hospitalization cost for neurosurgical procedures was $714.06, and the average amount paid to professionals per procedure was $145.28 with variations according to the type of practice (public or private) in which they were performed, the complexity of the procedure, and the Brazilian region. The mortality rate and mean length of stay for neurosurgical procedures were 11.37% and 10.15 days, respectively. There were 79 medical malpractice lawsuits in the studied period. In these lawsuits, 26.58% of the court decisions were unfavorable to the neurosurgeons, with a mean compensation per procedure 15 times higher than the median value paid for all professionals in a neurosurgical procedure. The spine subspecialty had more lawsuits, and the brain tumor subspecialty had the most expensive compensation.A lack of resources in public healthcare negatively impacts inpatient care. The mortality rate was 1.5 times higher in public practice than in private practice and was inversely proportional to the MTCs paid for the neurosurgical procedure. Patients with the lower educational levels associated with limited access to good medical care could reflect the lower plaintiff motivation in regions with a low gross domestic product and Human Development Index. In most cases, there is no understanding from either the patient or his family about the health-disease process, nor that there was medical malpractice committed by the physician to be sued.CONCLUSIONSThe socioeconomic inequalities and the population’s low awareness of their rights could explain the few malpractice cases reported in Brazil. The authors recommend better decisions regarding the investments to be made in neurosurgical procedures to reduce malpractice lawsuits.

Guidelines recommend a combined anticoagulant and antiplatelet approach for patients with atrial fibrillation (AF) after coronary stenting (CS) or acute coronary syndrome (ACS). Finding the optimal balance of reducing ischemic risk and minimizing bleeding risk is challenging. Recent trials have evaluated a variety of regimens for up to one year for AF patients after CS/ACS. Little empiric evidence exists about the best antithrombotic strategy beyond one year.In this review two key areas are covered. First, a summary of the overall risk and benefits of anticoagulant and antiplatelet therapy in patients with AF and CS or ACS is provided. Second, despite limited empiric evidence to guide therapeutic decisions for combined anticoagulant and antiplatelet therapy in patients with AF one year after CS/ACS we provide guidance for shared patient-physician decision making.The evidence is limited. For all patients with AF and stable CAD (≥1 year after CS or ACS) the risk for thromboembolism, cardiovascular events and bleeding should be assessed individually. For patients with low bleeding risk and high risk for cardiovascular events, antiplatelet therapy might be added to anticoagulant therapy.