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Background The relative efficacy and safety of ticagrelor and prasugrel based dual antiplatelet therapy strategies according to the platelet count (PC) in patients with acute coronary syndromes (ACS) have not been defined. Methods This is a posthoc analysis of the ISAR-REACT 5 trial, in which patients presenting with ACS were randomized to treatment with ticagrelor versus prasugrel. Patients were divided into quartiles according to PC. The primary endpoint was incidence of death, myocardial infarction, or stroke, and the safety endpoint was incidence of BARC (Bleeding Academic Research Consortium) type 3 to 5 bleeding at 12 months. Results A total of 3,943 patients with known PC (997 patients in quartile 1 (Q1), 1,003 in quartile 2 (Q2) [205 ± 10.3 × 109/L], 961 patients in quartile 3 (Q3) [241 ± 11.7 × 109/L], and 982 patients in quartile 4 (Q4) [317 ± 68.6 × 109/L]). There was no significant interaction between treatment arm (ticagrelor vs. prasugrel) and PC group with respect to primary endpoint (Q1: 8.8 vs. 6.3%, hazard ratio [HR] =1.41, 95% confidence interval [CI]: 0.89–2.23; p = 0.148; Q2: 9.9 vs. 5.8%, HR = 1.68, 95% CI: 1.06–2.66; p = 0.027; Q3: 7.8 vs. 5.5%, HR = 1.43, 95% CI: 0.87–2.37; p = 0.159; Q4: 10.1 vs. 10.1%, HR = 1.05, 95% CI: 0.71–1.57; p = 0.799; p for interaction [p int] = 0.482) and with respect to bleeding endpoint (Q1: 5.8 vs. 4.2%, HR = 1.41, 95% CI: 0.76–2.63; p = 0.279; Q2: 6.4 vs. 3.7%, HR = 1.62, 95% CI: 0.85–2.06; p = 0.140; Q3: 4.4 vs. 3.0%, HR = 1.53, 95% CI: 0.73–3.18; p = 0.258; Q4: 5.6 vs. 8.5%, HR = 0.67, 95% CI: 0.40–1.14; p = 0.138, p int = 0.102). Conclusions In this analysis, incidences of ischemic and bleeding events at 12 months are comparable across quartiles of platelet count.

Aims The effect of a prasugrel vs. a ticagrelor based strategy on total (including both first and recurrent) ischaemic and bleeding events in patients with acute coronary syndromes (ACS) has not been evaluated. The aim of this analysis was to investigate the treatment effect of a prasugrel vs. a ticagrelor based strategy in patients with ACS undergoing an invasive management strategy when both first and recurrent non-fatal ischaemic and bleeding events are taken into account. Methods and results This is a post-hoc analysis of the ISAR-REACT 5 randomized control trial, including all 4018 patients in the trial. The main clinical endpoints of interest included ischaemic events [myocardial infarction (MI) and stroke] and bleeding events [Bleeding Academic Research Consortium (BARC) type 3 to 5 bleeding]. An additional endpoint of interest was definite/probable stent thrombosis. The effect of the prasugrel vs. ticagrelor based strategies on these endpoints was evaluated on both time-to-first event and total events analyses. Patients in the prasugrel group had a lower risk of MI in comparison to the ticagrelor group on both time-to-first event [hazard ratio (HR) = 0.61; 95% confidence interval 0.44–0.85] and total events [HR = 0.62 (0.45–0.86)] analysis. The risk of BARC type 3 to 5 bleeding was comparable between the prasugrel and ticagrelor groups on both time-to-first event [HR = 0.96 (0.75–1.25)] and total events [HR = 0.99 (0.76–1.31)] analysis. Conclusion A prasugrel based strategy was associated with a reduction in total MI events in comparison to a ticagrelor based strategy in patients with ACS undergoing invasive assessment. Total BARC type 3 to 5 bleeding events were comparable between the two groups. Given the importance of this topic, future studies to confirm these findings would be welcome. ClinicalTrials.gov identifier: NCT01944800

The optimal antiplatelet therapy of patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) and chronic kidney disease (CKD) remains unknown. This study included 2,364 patients with NSTE-ACS undergoing predominantly percutaneous coronary intervention (PCI), who were randomized to ticagrelor or prasugrel in the ISAR-REACT 5 trial. Estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. The primary end point was 1-year mortality. Overall, there were 85 deaths (3.6%): 6 deaths (17.1%) in patients with eGFR30, 31 deaths (6.9%) in patients with eGFR 30 to60, 34 deaths (3.0%) in patients with eGFR 60 to90, and 14 deaths (2.0%) in patients with eGFR ≥90 ml/min/1.73 m

Pretransplant kidney graft biopsies have been suggested for organ quality assessment. Data on the association between donor proteinuria and organ quality of deceased donors are not available.In this prospective study, we analyzed 147 pretransplant kidney biopsies from 88 deceased adult donors procured and transplanted consecutively at the Medical University Vienna between July 2017 and May 2020. Lesions in each renal compartment were scored from 0 to 5 with each ascending score representing a 20% increase in organ damage. A chronic lesions score was calculated including glomerulosclerosis, intima fibrosis, hyalinosis, interstitial fibrosis, and tubular atrophy.The median chronic lesion score was 2 (interquartile range [IQR] 1-4) and the median donor urinary protein to creatinine ratio (UPCR) was 382 mg/dL (IQR 222-703). There was a positive correlation between UPCR and number of chronic lesions (β 0.15, 95% confidence interval, 0.03-0.28; P = 0.019). Biopsies with 2 or more lesions had a median UPCR of 486 mg/dL (IQR 251-717) compared with 274 mg/dL (IQR 211-556; P = 0.016) in biopsies with2 lesions. The risk for detection of 2 or more lesions rose by 18% for every log increase in UPCR (risk ratio 1.18, 95% confidence interval, 1.03-1.25; P = 0.017). Multivariable and sensitivity analysis revealed an independent and robust association between chronic lesions and UPCR.Donor UPCR is associated with chronic lesions in pretransplant deceased donor kidney graft biopsies. This finding justifies further investigation of donor proteinuria for the assessment of organ quality and outcome.

Diffuse large B-cell lymphoma (DLBCL) with aberrant coexpression of CD10+BCL6+MUM1+ (DLBCL-AE), classified as germinal center B cell (GCB) type by the Hans algorithm (HA), was genetically characterized. To capture the complexity of DLBCL-AE, we used an integrated approach that included gene expression profiling (GEP), fluorescence in situ hybridization, targeted gene sequencing, and copy number (CN) arrays. According to GEP, 32/54 (59%) cases were classified as GCB-DLBCL, 16/54 (30%) as activated B-cell (ABC) DLBCL, and 6/54 (11%) as unclassifiable. The discrepancy between HA and GEP was 41%. Three genetic subgroups were identified. Group 1 included 13/50 (26%) cases without translocations and mainly showing and ABC/MCD molecular profile. Group 2 comprised 11/50 (22%) cases with IRF4 alterations (DLBCL-IRF4), frequent mutations in IRF4 (82%) and NF-κB pathway genes (MYD88, CARD11, and CD79B), and losses of 17p13.2. Five cases each were classified as GCB- or ABC-type. Group 3 included 26/50 (52%) cases with 1 or several translocations in BCL2/BCL6/MYC/IGH, and GCB/EZB molecular profile predominated. Two cases in this latter group showed complex BCL2/BCL6/IRF4 translocations. DLBCL-IRF4 in adults showed a similar copy number profile and shared recurrent CARD11 and CD79B mutations when compared with LBCL-IRF4 in the pediatric population. However, adult cases showed higher genetic complexity, higher mutational load with frequent MYD88 and KMT2D mutations, and more ABC GEP. IRF4 mutations were identified only in IRF4-rearranged cases, indicating its potential use in the diagnostic setting. In conclusion, DLBCL-AE is genetically heterogeneous and enriched in cases with IRF4 alterations. DLBCL-IRF4 in adults has many similarities to the pediatric counterpart.

Introduction: Trials investigating aspirin omission in patients taking oral anticoagulation (OAC) after percutaneous coronary intervention (PCI) or acute coronary syndrome (ACS) were not powered to assess rates of major bleeding or ischemic events.Methods: We performed an updated meta-analysis and network analysis of randomized trials comparing treatment with or without aspirin in patients taking OAC and a P2Y12-inhibitor after PCI or ACS. The primary outcome was TIMI major bleeding.Results: Five trials enrolling 11,542 patients allocated to antithrombotic regimens omitting (n = 5795) or including aspirin (n = 5747) were included. Aspirin omission was associated with a lower risk of TIMI major bleeding (RR = 0.56, 95% CI [0.44-0.71]; P < 0.001) but a trend towards a higher risk of MI (RR = 1.21, 95% CI [0.99-1.47]; P = 0.06), which was significantly higher when only non-vitamin K antagonist OAC (NOAC)-based trials were considered (Pinteraction = 0.02). The risk of stent thrombosis was comparable with both strategies (RR = 1.29, 95% CI [0.87-1.90]; P = 0.20), with a trend towards a higher risk of ST with aspirin omission when only NOAC-based trials were considered (Pinteraction = 0.06). Risks of stroke and death were similar with both strategies. Network meta-analysis ranked dabigatran (low dose) without aspirin as the best strategy for bleeding reduction (P-score = 0.86) and apixaban with aspirin as the best strategy for MI reduction (P-score = 0.66).Conclusions: In patients taking OAC after PCI or ACS, aspirin omission is associated with a lower risk of TIMI major bleeding, with a numerically increased risk of MI, which is statistically significant when only NOAC-based trials are considered. This supports individualization of the treatment regimen based on patient risk.

Objective The aim of this study was to assess the association between high on-aspirin treatment platelet reactivity (HAPR) and the subsequent risk of restenosis after percutaneous coronary intervention (PCI) with predominantly drug-eluting stents. Background The association between HAPR and subsequent risk of restenosis after PCI is unclear. Methods This study included 4839 patients undergoing PCI (02/2007–12/2011) in the setting of the Intracoronary Stenting and Antithrombotic Regimen-ASpirin and Platelet Inhibition (ISAR-ASPI) registry. Platelet function was assessed with impedance aggregometry using the multi-plate analyzer immediately before PCI and after intravenous administration of aspirin (500 mg). The primary outcome was clinical restenosis, defined as target lesion revascularization at 1 year. Secondary outcomes included binary angiographic restenosis and late lumen loss at 6- to 8-month angiography. Results The upper quintile cut-off of platelet reactivity measurements (191 AU × min) was used to categorize patients into a group with HAPR (platelet reactivity > 191 AU × min; n = 952) and a group without HAPR (platelet reactivity ≤ 191 AU × min; n = 3887). The primary outcome occurred in 94 patients in the HAPR group and 405 patients without HAPR (cumulative incidence, 9.9% and 10.4%; HR = 0.96, 95% CI 0.77–1.19; P = 0.70). Follow-up angiography was performed in 73.2% of patients. There was no difference in binary restenosis (15.2% vs. 14.9%; P = 0.79) or late lumen loss (0.32 ± 0.57 vs. 0.32 ± 0.59 mm; P = 0.93) between patients with HAPR versus those without HAPR. Conclusions This study did not find an association between HAPR, measured at the time of PCI, and clinical restenosis at 1 year after PCI. Graphical abstract

Background: Immature or reticulated platelets are associated with impaired efficacy of antiplatelet drugs and adverse events in cardiovascular patients. Their role as a predictive biomarker in patients with acute coronary syndrome treated with potent P2Y 12 receptor inhibitors is not fully understood. We aimed to prospectively evaluate reticulated platelets as a predictor of the primary end point of the ISAR-REACT 5 trial consisting of death, myocardial infarction, or stroke at 1 year in patients with acute coronary syndrome randomized to prasugrel or ticagrelor. Methods: Immature platelet fraction (IPF) was assessed within 48 hours after randomization. Patients were divided based on the IPF median values: the IPF high group included patients with IPF>median and the IPF low group included patients with IPF≤median. Platelet aggregation was assessed using the Multiplate Analyzer and was correlated to IPF. Results: Five hundred seventy-seven patients were included in the study. IPF values in % (median [interquartile range]) within the first 48 hours did not differ between the two study groups: 3.6 (2.5–5.2)% in the prasugrel group and 3.6 (2.5–5.4)% in the ticagrelor group ( P =0.882). The incidence of the primary end point was significantly higher in the IPF high (IPF>3.6%) group compared with the IPF low (IPF ≤ 3.6%) group: 13.0% versus 7.2% (HR adj , 1.74 [1.02–3.00]; P =0.044), independently from the assigned drug ( P int =0.159). No significant association between IPF and BARC 3 to 5 bleeding was observed. ADP-induced platelet aggregation correlated significantly with IPF in patients treated with prasugrel ( r =0.22; P =0.005) while no correlation was detected in patients treated with ticagrelor ( r =0.09; P =0.257). Conclusions: Independently from drug treatment, IPF was associated with the primary end point and therefore is a promising biomarker for the prediction of adverse cardiovascular events in patients with acute coronary syndrome treated with prasugrel or ticagrelor. Registration: https://www.clinicaltrials.gov ; Unique identifier: NCT01944800.

Objectives The aim of this study was to assess the safety and efficacy of ticagrelor versus prasugrel for patients with acute coronary syndrome (ACS) according to their estimated glomerular filtration rates (eGFRs). Background The outcomes of ticagrelor versus prasugrel in patients with ACS according to eGFR have not been defined. Methods Patients (n = 4,012) were categorized into 3 groups: low eGFR ( Results Patients with low eGFRs had a higher risk for the primary endpoint compared with patients with intermediate eGFRs (adjusted HR: 1.89; 95% CI: 1.46-2.46]) and those with high eGFRs (adjusted HR: 2.33; 95% CI: 1.57-3.46). A risk excess for low eGFR was also observed for bleeding (adjusted HR: 1.55 [95% CI: 1.12-2.13] vs intermediate eGFR; adjusted HR: 1.59 [95% CI: 1.01-2.50] vs high eGFR). However, eGFR did not affect the relative efficacy and safety of ticagrelor versus prasugrel. In patients with low eGFR, the primary endpoint occurred in 20.5% with ticagrelor and in 14.7% with prasugrel (HR: 1.47; 95% CI: 1.04-2.08; P = 0.029); there was no significant difference in bleeding. Conclusions These results show that among patients with ACS, reduction of eGFR is associated with increased risk for ischemic and bleeding events but has no significant impact on the relative efficacy and safety of ticagrelor versus prasugrel. (Prospective, Randomized Trial of Ticagrelor Versus Prasugrel in Patients With Acute Coronary Syndrome [ISAR-REACT 5]; NCT01944800 )

Background The efficacy and safety of ticagrelor versus prasugrel according to smoking status in patients with acute coronary syndromes (ACS) are not known. We assessed the efficacy and safety of ticagrelor versus prasugrel according to smoking status in patients with ACS undergoing invasive management. Methods This pre-specified analysis of the ISAR-REACT 5 trial included 1349 smokers and 2652 nonsmokers randomized to receive ticagrelor or prasugrel. The primary endpoint was the incidence of death, myocardial infarction, or stroke; the secondary endpoint was the incidence of Bleeding Academic Research Consortium (BARC) type 3 to 5 bleeding (both endpoints assessed at 12 months). Results There was no significant treatment arm-by-smoking status interaction regarding the efficacy outcome. The primary endpoint occurred in 47 patients (7.0%) in the ticagrelor group and 41 patients (6.2%) in the prasugrel group in smokers (hazard ratio [HR] = 1.15; 95% confidence interval [CI] 0.76–1.75; P = 0.510) and in 133 patients (10.2%) in the ticagrelor group and 94 patients (7.2%) in the prasugrel group in nonsmokers (HR = 1.44 [1.10–1.87]; P = 0.007; P for interaction = 0.378). The secondary endpoint occurred in 27 patients (4.6%) in the ticagrelor group and 33 patients (5.6%) in the prasugrel group in smokers (HR = 0.81 [0.49–1.35]; P = 0.412) and in 66 patients (6.0%) in the ticagrelor group and 46 patients (4.4%) in the prasugrel group in nonsmokers (HR = 1.38 [0.94–2.01]; P = 0.097). Conclusions In patients with ACS undergoing an invasive management strategy, the smoking status did not significantly interact with the relative treatment effect of ticagrelor vs. prasugrel. Clinical trial registration NCT01944800

Background Whether plasma levels of soluble glycoprotein VI (sGPVI) are able to predict ischemic or bleeding risk in patients with chronic coronary syndrome (CCS) undergoing percutaneous coronary intervention (PCI) is not known. The objective of this study was to answer this question. Material and methods The present study included 317 patients out of 334 patients of the ISAR-PLASTER trial (randomized trial of 2 doses of revacept vs. placebo), who underwent PCI for CCS and had baseline plasma sGPVI levels available. Patients were categorized into three groups according to tertiles of sGPVI: low (n = 106; sGPVI ≤ 9.5 ng/ml), intermediate (n = 106; sGPVI ≤ 16.2 ng/ml) and high tertile of sGPVI (n = 105; sGPVI ≥ 16.5 ng/ml). The composite of death and myocardial injury (MI) at 48 hours after randomization served as a measure of ischemic risk, and Bleeding Academic Research Consortium (BARC) type 1 to 5 bleeding at 30 days as a measure of bleeding risk. Results and conclusions Baseline plasma levels of sGPVI (before PCI and revacept administration) correlated with bleeding (bleeding incidence among low, intermediate and high sGPVI tertile: 11.8%, 13.6%, and 25.8%, respectively; P = 0.005), but not with ischemic events (incidence of death/MI among low, intermediate and high sGPVI tertile: 25.0%, 21.9%, and 26.9%, respectively; P = 0.70). Revacept did not interact with these associations. Elevated plasma sGPVI levels are associated with an increased risk of bleeding but not ischemic complications after PCI in patients with CCS. Funding German Center for Cardiovascular Research, Deutsches Herzzentrum München, Federal Ministry of Education and Research, and advanceCOR.

Background: The relative efficacy and safety of more potent P2Y 12 inhibitors in patients with acute coronary syndrome and high bleeding risk (HBR) undergoing percutaneous coronary intervention remains unclear. We aimed to study the treatment effect of ticagrelor and prasugrel in percutaneous coronary intervention patients presenting with acute coronary syndrome and HBR. Methods: This post hoc analysis of the ISAR-REACT 5 trial (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5) included patients with acute coronary syndrome undergoing percutaneous coronary intervention, randomized to ticagrelor or prasugrel, in whom HBR was defined as per Academic Research Consortium criteria. The primary (efficacy) end point was the composite of all-cause death, myocardial infarction, or stroke. The secondary (safety) end point was Bleeding Academic Research Consortium type 3 to 5 bleeding. Outcomes were assessed 12 months after randomization. Results: Out of the 3239 patients included in this analysis, 486 fulfilled the criteria for Academic Research Consortium-HBR definition (HBR group; ticagrelor, n=230 and prasugrel, n=256), while 2753 did not (non-HBR group; ticagrelor, n=1375 and prasugrel, n=1378). Compared with the non-HBR group, the HBR group had a higher risk for the primary (hazard ratio [HR]=3.57 [95% CI, 2.79–4.57]; P P P for interaction=0.12) or secondary ( P for interaction=0.80) end points. Conclusions: In patients with acute coronary syndrome undergoing percutaneous coronary intervention, HBR status increased both ischemic and bleeding risk without significant impact on the relative efficacy and safety of either ticagrelor or prasugrel. These results warrant confirmation in larger cohorts. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01944800.

Since 2008, legislative initiatives for climate protection and reduced dependency on fossil resource imports led to the introduction of biofuels as CO2-reduced alternatives in the heating oil sector. In the case of biodiesel, the oil industry or its customers were confronted with accelerated and escalating microbial contaminations during heating oil storage. Since then, other fuel alternatives, like hydrogenated vegetable oils, gas-to-liquid products (GtL), or Oxymethylenether (OME) have been or will be developed and potentially introduced to the market. In this study, we use online monitoring of microbial CO2 production and the simulation of onset of microbial contamination to investigate the contamination potential of fuel alternatives during storage. As reference and blends, fossil heating oils of various refineries, in the course of this from various crude oils, and refinery processes reveal considerable variation in potential microbial activity. Oxymethylene ethers have an antimicrobial effect, while various forms of biodiesel confirm the promotion of microbial activity and diversity. The paraffinic Fischer-Tropsch products and biogenic hydrogenation products demonstrate high resistance to microbial contamination despite allowing microbial diversity. Through an array of analytics, including advanced chromatography coupled mass spectrometry, elemental analysis, and microbial sequencing, we can discuss critical fuel properties that promote or inhibit microbial contaminations. In summary, novel, non-fossil heating oils show different strengths and weaknesses for long-term storage. Designing blends for microbial activity reduced long-term storage might be an option. While being niche products, these fuels will contribute to the rapid reduction of fossil resource use.

Background: Data on the comparative efficacy and safety of ticagrelor versus prasugrel in patients with ST-segment–elevation myocardial infarction undergoing primary percutaneous coronary intervention are limited. We assessed the efficacy and safety of ticagrelor versus prasugrel in a head-to-head comparison in patients with ST-segment–elevation myocardial infarction undergoing primary percutaneous coronary intervention. Methods: In this prespecified subgroup analysis, we included 1653 patients with ST-segment–elevation myocardial infarction randomized to receive ticagrelor or prasugrel in the setting of the ISAR REACT-5 trial (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5). The primary end point was the incidence of death, myocardial infarction, or stroke at 1 year after randomization. The secondary end point was the incidence of bleeding defined as BARC (Bleeding Academic Research Consortium) type 3 to 5 bleeding at 1 year after randomization. Results: The primary end point occurred in 83 patients (10.1%) in the ticagrelor group and in 64 patients (7.9%) in the prasugrel group (hazard ratio, 1.31 [95% CI, 0.95–1.82]; P =0.10). One-year incidence of all-cause death (4.9% versus 4.7%; P =0.83), stroke (1.3% versus 1.0%; P =0.46), and definite stent thrombosis (1.8% versus 1.0%; P =0.15) did not differ significantly in patients assigned to ticagrelor or prasugrel. One-year incidence of myocardial infarction (5.3% versus 2.8%; hazard ratio, 1.95 [95% CI, 1.18–3.23]; P =0.010) was higher with ticagrelor than with prasugrel. BARC type 3 to 5 bleeding occurred in 46 patients (6.1%) in the ticagrelor group and in 39 patients (5.1%) in the prasugrel group (hazard ratio, 1.22 [95% CI, 0.80–1.87]; P =0.36). Conclusions: In patients with ST-segment–elevation myocardial infarction undergoing primary percutaneous coronary intervention, there was no significant difference in the primary end point between prasugrel and ticagrelor. Ticagrelor was associated with a significant increase in the risk for recurrent myocardial infarction. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01944800.

BACKGROUND AND AIMS The apathogenic and torque teno virus (TTV) is associated with the state of immunosuppression in solid organ transplant recipients. After kidney transplantation, quantification of TTV viral load may serve as a risk stratification tool for allograft rejection and infectious events. Besides a robust and independent association between recipient age, sex and TTV load, respectively, limited data exists on other potential determinants of TTV load. This trial was designed to analyse the association between TTV and detailed recipient and donor baseline characteristics and clinical follow-up parameters. METHOD This retrospective analysis included all 386 consecutive adult recipients of a kidney allograft transplanted between 1 January 2016 and 30 June 2018 at the Medical University Vienna from the prospective observational TTV-POET trial (institutional review board approval number: 1785/2016; German Clinical Trials Registry number: DRKS00012335). For the present analysis, we included TTV measures before transplantation (d0), at month 1 (m1), at month 3 (m3) and at month 12 (m12) after transplantation. TTV DNA was extracted from patient plasma and assessed by real-time PCR with laboratory-developed primers. TTV load was associated with recipient and donor baseline characteristics and follow-up data. RESULTS The median recipient and donor age at transplantation was 55 years. A total of 135 (35%) kidney allograft recipients were female; 74 patients (19%) had a history of prior kidney transplantation; and 318 patients (82%) received a deceased donor kidney transplant. A total of 34 patients (9%) had pre-formed donor-specific antibodies (DSA); 19 patients (5%) received an AB0-incompatible transplant. For the whole cohort, 1-year patient survival was 95.6% and 1-year death censored graft survival was 94.8%. Baseline TTV load (d0) was lower in female recipients (P = 0.003) and higher in older recipients {β 0.033, [95% confidence interval (95% CI) 0.002–0.066]; P = 0.039}. Baseline TTV load was not associated with recipient body mass index and a history of immunological causes of end-stage renal disease and diabetes mellitus, respectively. TTV load within the first year after kidney transplantation did not show an association with the prevalence of preformed DSA, induction treatment, AB0-incompatibility and HLA-mismatch, respectively. Our trial detected an association between donor age and TTV load. Recipients from older donors showed higher TTV loads (m1, β 0.037, 95% CI 0.008–0.065, P = .01; m3, β 0.04, 95% CI 0.012–0.068, P = .005; m12, β 0.065, 95% CI 0.028–0.01, P = .001). There was no association between TTV load during the first year after transplantation and donor sex. When investigating the association between TTV load and clinical follow-up data, TTV levels showed a negative correlation with peripheral blood leukocyte and lymphocyte counts during the first year after transplantation [lymphocytes: m1, β –0.867, 95% CI –1.367–0.364, P = .01; m3, β –0.985, 95% CI –1.709–0.260, P = .008; m12, β –1.304, 95% CI –2.156–0.452, P = .003; data on leukocytes not shown). These findings might reflect the role of lymphocytes for TTV control. Additionally, TTV viral load negatively correlated with the estimated glomerular filtration rate (MDRD) within the first year after kidney transplantation (m1, β –0.043, 95% CI –0.066–0.02, P < .001; m3, β –0.024, 95% CI –0.049–0.001, P = .06; m12, β –0.078, 95% CI –0.111–0.045, P < .001). One might speculate that a higher eGFR might be a proxy for a healthier donor being more capable of controlling TTV infection. TTV viral load was associated with tacrolimus trough levels in month 12 after transplantation (β 1.262, 95% CI 0.0221–0.250; P = .019), but not with the amount of mycophenolic acid dosage. CONCLUSION This study revealed an association between TTV viral load and distinct baseline donor and recipient characteristics and clinical follow-up data, including kidney function. Further analysis, especially longitudinal assessment of TTV levels, may help to further dissect the interplay between TTV viral load and the state of immunosuppression in patients undergoing kidney transplantation.

Objectives To assess the efficacy and safety of ticagrelor versus prasugrel in patients with acute coronary syndrome (ACS) presenting during off- and on-hours. Background The efficacy and safety of ticagrelor versus prasugrel in patients with ACS according to time of hospital presentation remain unknown. Methods This post hoc analysis of the ISAR-REACT 5 trial included 1565 patients with ACS presenting off-hours and 2453 patients presenting on-hours, randomized to ticagrelor or prasugrel. The primary endpoint was a composite of death, myocardial infarction, or stroke; the safety endpoint was Bleeding Academic Research Consortium (BARC) type 3–5 bleeding, both at 12 months. Results The primary endpoint occurred in 80 patients (10.4%) in the ticagrelor group and 57 patients (7.3%) in the prasugrel group in patients presenting off-hours (hazard ratio [HR] = 1.45; 95% confidence interval [CI] 1.03–2.03; P = 0.033), and 104 patients (8.5%) in the ticagrelor group and 80 patients (6.7%) in the prasugrel group in patients presenting on-hours (HR = 1.29 [0.97–1.73]; P = 0.085), without significant treatment arm-by-presentation time interaction (Pint = 0.62). BARC type 3 to 5 bleeding occurred in 35 patients (5.1%) in the ticagrelor group and 37 patients (5.3%) in the prasugrel group (P = 0.84) in patients presenting off-hours, and 60 patients (5.9%) in the ticagrelor group and 43 patients (4.6%) in the prasugrel group in patients presenting on-hours (P = 0.17). Conclusions In patients with ACS planned to undergo an invasive treatment strategy, time of presentation (off-hours vs. on-hours) does not interact significantly with the relative efficacy and safety of ticagrelor vs. prasugrel. Clinical trial registration. NCT01944800. Graphical abstract

Background Current guidelines recommend intensified platelet inhibition by prasugrel or ticagrelor in patients with unstable angina (UA) or non-ST-segment elevation (NSTE) myocardial infarction (MI). Objectives This study sought to investigate the benefits and risks of ticagrelor as compared with prasugrel in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) and planned invasive management. Methods This post hoc analysis combines the pre-specified subgroups of UA and NSTEMI of the randomized ISAR-REACT 5 trial. It included 1,179 patients assigned to ticagrelor and 1,186 assigned to prasugrel. Ticagrelor was started immediately after randomization and prasugrel after coronary angiography. The primary endpoint was a composite of death, MI, or stroke during 1-year follow-up, and the safety endpoint was Bleeding Academic Research Consortium class 3–5. Results The primary endpoint was reached in 101 (8.7%) patients in the ticagrelor and in 73 (6.3%) patients in the prasugrel group (hazard ratio [HR]: 1.41; 95% confidence interval [CI]: 1.04 to 1.90). The HR for all-cause death was 1.43 (95% CI: 0.93 to 2.21) and that for MI 1.43 (95% CI: 0.94 to 2.19). The safety endpoint occurred in 49 (5.2%) patients in the ticagrelor and in 41 (4.7%) patients in the prasugrel group (HR: 1.09; 95% CI: 0.72 to 1.65). Landmark analysis revealed persistence of the efficacy advantage with prasugrel after the first month. Conclusions In patients with NSTE-ACS, we found that prasugrel was superior to ticagrelor in reducing the combined 1-year risk of death, MI, and stroke without increasing the risk of bleeding. Due to the post hoc nature of the analysis, these findings need confirmation by further studies. (Prospective, Randomized Trial of Ticagrelor Versus Prasugrel in Patients With Acute Coronary Syndrome; NCT01944800 )

Objectives The aim of this study was to assess the efficacy and safety of ticagrelor versus prasugrel in patients with diabetes mellitus (DM) presenting with acute coronary syndromes (ACS)...

Objective: Atrial cardiomyopathy (ACM) is associated with development of AF, left atrial (LA) thrombogenesis, and stroke. Diagnosis of ACM is feasible using both echocardiographic LA strain imaging and measurement of the amplified p-wave duration (APWD) in digital 12-lead-ECG. We sought to determine the thresholds of LA global longitudinal strain (LA-GLS) and APWD that identify patients with AF at risk for LA appendage (LAA) thrombogenesis. Methods: One hundred and twenty-eight patients with a history of AF were included. Left atrial appendage maximal flow velocity (LAA-Vel, in TEE), LA-GLS (TTE), and APWD (digital 12-lead-ECG) were measured in all patients. ROC analysis was performed for each method to determine the thresholds for LA-GLS and the APWD, enabling diagnosis of patients with LAA-thrombus. Results: Significant differences in LA-GLS were found during both rhythms (SR and AF) between the thrombus group and control group: LA-GLS in SR: 14.3 ± 7.4% vs. 24.6 ± 9.0%, p < 0.001 and in AF: 11.4 ± 4.2% vs. 16.1 ± 5.0%, p = 0.045. ROC analysis revealed a threshold of 17.45% for the entire cohort (AUC 0.82, sensitivity: 84.6%, specificity: 63.6%, Negative Predictive Value (NPV): 94.3%) with additional rhythm-specific thresholds: 19.1% in SR and 13.9% in AF, and a threshold of 165 ms for APWD (AUC 0.90, sensitivity: 88.5%, specificity: 75.5%, NPV: 96.2%) as optimal discriminators of LAA-thrombus. Moreover, both LA-GLS and APWD correlated well with the established contractile LA-parameter LAA-Vel in TEE (r = 0.39, p < 0.001 and r = −0.39, p < 0.001, respectively). Conclusion: LA-GLS and APWD are valuable diagnostic predictors of left atrial thrombogenesis in patients with AF.

Aims To assess whether the efficacy and safety of ticagrelor vs. prasugrel in patients with acute coronary syndromes (ACSs) are influenced by pre-admission treatment with aspirin and/or clopidogrel. Methods and results Patients (n = 4018) were categorized into two groups: pre-admission aspirin and/or clopidogrel group (n = 1455) and no pre-admission aspirin or clopidogrel group (n = 2563). The primary endpoint was the composite of all-cause death, myocardial infarction, or stroke; the secondary safety endpoint was Bleeding Academic Research Consortium (BARC) type 3–5 bleeding, both at 1 year. Patients in the pre-admission aspirin and/or clopidogrel group had a higher risk of ischaemic events, but a similar risk of bleeding to patients in the no pre-admission aspirin or clopidogrel group (cumulative incidences 10.5% vs. 6.7%, and 5.7% vs. 5.7%, respectively). The primary endpoint occurred in 81/717 patients assigned to ticagrelor and 69/738 patients assigned to prasugrel in the pre-admission aspirin and/or clopidogrel group [11.5% vs. 9.5%; hazard ratio (HR) = 1.23; 95% confidence interval (CI) 0.89–1.69], and in 103/1295 patients assigned to ticagrelor and 68/1268 patients assigned to prasugrel in the no pre-admission aspirin or clopidogrel group [8.0% vs. 5.4%; HR = 1.50 (1.10–2.03); Pint = 0.38]. BARC type 3–5 bleeding events did not differ between ticagrelor and prasugrel in patients in the pre-admission aspirin and/or clopidogrel (6.2% vs. 4.5%) or no pre-admission aspirin or clopidogrel (5.3% vs. 5.1%) group (Pint = 0.54). Conclusion In patients with ACS, pre-admission therapy with aspirin and/or clopidogrel has no influence on the relative efficacy and safety of ticagrelor and prasugrel.

BACKGROUND Whether there are differences in the risk profile and treatment effect in patients recruited in a low recruitment center (LRC) versus patients recruited in a high recruitment center (HRC) in a randomized multicenter trial remains unknown. METHODS AND RESULTS This study included 4018 patients with acute coronary syndrome recruited in the ISAR‐REACT 5 (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5) trial. The primary end point was a composite of all‐cause death, myocardial infarction, or stroke. Overall, 3011 patients (75%) were recruited in the HRCs (7 centers recruiting 258 to 628 patients; median, 413 patients) and 1007 patients (25%) were recruited in the LRCs (16 centers recruiting 5 to 201 patients; median, 52 patients). Patients recruited in the LRCs had more favorable cardiovascular risk profiles than patients recruited in the HRCs. The primary end point occurred in 72 patients in the LRCs and 249 patients in the HRCs (cumulative incidence, 7.3% and 8.4%; P =0.267). All‐cause mortality was lower among patients recruited in the LRCs (n=29) than among patients recruited in the HRCs (n=134; cumulative incidence 2.9% versus 4.5%; P =0.031). There was no significant interaction between the treatment effect of ticagrelor versus prasugrel and patient recruitment category (LRC versus HRC) regarding the primary efficacy end point (LRC: hazard ratio [HR], 1.42 [95% CI, 0.89–2.28]; HRC: HR, 1.33 [95% CI, 1.04−1.72]; P for interaction=0.800). CONCLUSIONS Patients with acute coronary syndrome recruited in a LRC appear to have more favorable cardiovascular risk profiles and lower 1‐year mortality rates compared with patients recruited in a HRC. The recruitment volume did not interact with the treatment effect of ticagrelor versus prasugrel. REGISTRATION URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01944800.

Objectives The aim of this study was to assess the safety and efficacy of ticagrelor versus prasugrel for patients with acute coronary syndrome (ACS) according to their glomerular filtration rate (GFR). Background The outcomes of ticagrelor versus prasugrel in patients with ACS according to GFR have not been defined. Methods Patients (n=3985) with GFR available were categorized in three groups according to the tertiles of GFR. The primary endpoint was a composite of all-cause death, myocardial infarction and stroke at 1 year. Results The primary endpoint occurred significantly more often in patients with low GFR compared to high GFR as well as in patients with low GFR compared to intermediate GFR (picture 1). Patients in the lowest GFR group had significantly higher ischemic and bleeding risks than patients in the intermediate (hazard ratio [HR] 1.93 and 1.68) or high GFR groups (HR 3.52 and 2.96). In the group with low GFR, the primary endpoint occurred in 103 of 677 ticagrelor patients (15.4%) and in 72 of 652 prasugrel patients (11.2%; (HR=1.45, [1.07–1.96], p=.016, picture 2). In addition, each single component of the primary endpoint and stent thrombosis were numerically lower with prasugrel compared with ticagrelor. Occurrence of myocardial infarction was 3.7% with prasugrel compared to 6.6% with ticagrelor (p=0.019). BARC 3–5 bleeding events were similar with ticagrelor and prasugrel (8.8% versus 7.1%, p=0.278). In the intermediate and high GFR group the primary endpoint and bleeding events were similar between prasugrel and ticagrelor. Conclusions The incidence of a composite endpoint (all-cause death, myocardial infarction or stroke) occurred less frequently in patients who received prasugrel compared to patients who received ticagrelor in the low GFR population, whereas rate of bleeding events was similar. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Supported by a grant (FKZ 81X1600501) from the German Center for Cardiovascular Research and the Deutsches Herzzentrum München, Germany. Primary endpoint according to GFRLow GFR: Prasugrel versus Ticagrelor

Background The efficacy and safety of ticagrelor versus prasugrel according to smoking status in patients with acute coronary syndromes (ACS) are not known. Purpose The aim of this study was to assess the efficacy and safety of ticagrelor versus prasugrel according to smoking status in patients with ACS undergoing invasive evaluation. Methods This pre-specified analysis of the ISAR-REACT 5 trial included 1349 smokers and 2652 nonsmokers randomised to receive ticagrelor or prasugrel. The primary endpoint was the incidence of death, myocardial infarction, or stroke; the secondary endpoint was the incidence of Bleeding Academic Research Consortium (BARC) type 3 to 5 bleeding. Both endpoints were assessed at 12 months after randomisation. Results There was no significant treatment arm-by-smoking status interaction regarding the efficacy outcome. The primary endpoint occurred in 47 patients (7.0%) in the ticagrelor group and 41 patients (6.2%) in the prasugrel group in smokers (hazard ratio [HR]=1.15; 95% confidence interval [CI] 0.76–1.75; P=0.510) and in 133 patients (10.2%) in the ticagrelor group and 94 patients (7.2%) in the prasugrel group in nonsmokers (HR=1.44 [1.10–1.87], P=0.007; Pint=0.378). The secondary endpoint occurred in 27 patients (4.6%) in the ticagrelor group and 33 patients (5.6%) in the prasugrel group in smokers (HR=0.81 [0.49–1.35]; P=0.412) and in 66 patients (6.0%) in the ticagrelor group and 46 patients (4.4%) in the prasugrel group in nonsmokers (HR=1.38 [0.94–2.01]; P=0.097). Conlusions Although there was no significant interaction between smoking and treatment effect, the present findings suggest a greater advantage of prasugrel over ticagrelor in nonsmoker vs. smoker patients with ACS. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): German Centre for Cardiovascular Research;Deutsches Herzzentrum München, Germany

Background The efficacy and safety of ticagrelor versus prasugrel in patients with acute coronary syndromes (ACS) according to body mass index (BMI) remain unknown. Purpose To assess the efficacy and safety of ticagrelor versus prasugrel in patients with ACS according to BMI. Methods This post-hoc analysis of the ISAR-REACT 5 trial included 3987 patients with BMI data available. BMI was grouped in 3 categories: low (BMI Results There was no significant treatment arm-by-BMI interaction regarding the primary endpoint (Pint=0.578). However, the primary endpoint occurred in 63 patients assigned to ticagrelor and 39 patients assigned to prasugrel in the low BMI group (11.7% vs. 7.5%; hazard ratio [HR]=1.62; 95% confidence interval [CI], 1.09–2.42; P=0.018), 78 patients assigned to ticagrelor and 58 patients assigned to prasugrel in the intermediate BMI group (8.3% vs. 6.2%; HR=1.36 [0.97–1.91]; P=0.076), and 43 patients assigned to ticagrelor and 37 patients assigned to prasugrel in the high BMI group (8.6% vs. 7.3%; HR=1.18 [0.76–1.84]; P=0.451). BARC type 3 to 5 bleeding events did not differ between ticagrelor and prasugrel in patients with low (6.5% vs. 6.6%), intermediate (5.6% vs. 5.0%), or high (4.4% vs. 2.8%) BMI. Conclusions BMI of patients with ACS did not impact significantly on the treatment effect of ticagrelor vs. prasugrel in terms of both efficacy and safety. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): German Center for Cardiovascular Research;Deutsches Herzzentrum München, Germany

BACKGROUND The prognostic value of in-hospital haemoglobin drop in patients with acute coronary syndrome (ACS) undergoing invasive therapy remains insufficiently investigated. MATERIALS AND METHODS This observational study included 3838 patients with ACS with admission and in-hospital nadir haemoglobin values available. Haemoglobin drop was defined as a positive difference between admission and nadir haemoglobin values. The primary endpoint was one-year all-cause mortality. RESULTS In-hospital haemoglobin drop occurred in 3142 patients (82%). Patients were categorized into 4 groups: no haemoglobin drop (n = 696 patients)

The efficacy and safety of ticagrelor vs prasugrel in patients with acute coronary syndromes (ACS) according to body mass index (BMI) remain unstudied. We assessed the efficacy and safety of ticagrelor vs prasugrel in patients with ACS according to BMI.Patients (n=3987) were grouped into 3 categories: normal weight (BMI 25kg/mThe primary endpoint occurred in 63 patients assigned to ticagrelor and 39 patients assigned to prasugrel in the normal weight group (11.7% vs 7.5%; HR, 1.62; 95%CI, 1.09-2.42; P=.018), 78 patients assigned to ticagrelor and 58 patients assigned to prasugrel in the overweight group (8.3% vs 6.2%; HR, 1.36; 95%CI, 0.97-1.91; P=.076), and 43 patients assigned to ticagrelor and 37 patients assigned to prasugrel in the obesity group (8.6% vs 7.3%; HR, 1.18; 95%CI, 0.76-1.84; P=.451). The 1-year incidence of bleeding events did not differ between ticagrelor and prasugrel in patients with normal weight (6.5% vs 6.6%; P=.990), overweight (5.6% vs 5.0%; P=.566) or obesity (4.4% vs 2.8%; P=.219). There was no significant treatment arm-by-BMI interaction regarding the primary endpoint (PIn patients with ACS, BMI did not significantly impact the treatment effect of ticagrelor vs prasugrel in terms of efficacy or safety.NCT01944800.

Importance It is unclear whether ticagrelor or prasugrel hydrochloride is superior for patients with acute coronary syndrome (ACS) treated with percutaneous coronary intervention (PCI). Objective To assess the safety and efficacy of ticagrelor vs prasugrel for patients with ACS treated with PCI. Design, Setting, and Participants A prespecified analysis was performed of a postrandomization subgroup of 3377 patients who presented with ACS and were treated with PCI in the investigator-initiated, multicenter, phase 4, open-label Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5 randomized clinical trial, conducted from September 1, 2013, to February 28, 2018. Statistical analysis was performed from September 1, 2020, to January 30, 2021. Analysis was performed according to the intention-to-treat principle. Interventions Patients were randomly assigned to a ticagrelor-based or prasugrel-based strategy. This analysis focuses on the subgroup of patients who underwent PCI that was formed after randomization. Main Outcomes and Measures The primary end point was a composite consisting of all-cause death, myocardial infarction, or stroke at 12 months. The safety end point was Bleeding Academic Research Consortium (BARC) type 3 to 5 bleeding. Results The ticagrelor group comprised 1676 patients (1323 men [78.9%]; mean [SD] age, 64.4 [12.0] years), and the prasugrel group comprised 1701 patients (1341 men [78.8%]; mean [SD] age, 64.7 [12.0] years). The primary end point occurred for 162 patients (9.8%) in the ticagrelor group and 120 patients (7.1%) in the prasugrel group (hazard ratio [HR], 1.41; 95% CI, 1.11-1.78;P = .005). Myocardial infarction occurred in 88 patients (5.3%) in the ticagrelor group compared with 55 patients (3.8%) in the prasugrel group (HR, 1.67; 95% CI, 1.19-2.34;P = .003). The safety end point, BARC type 3 to 5 bleeding, occurred in 84 of 1672 patients (5.3%) in the ticagrelor group and 78 of 1680 patients (4.9%) in the prasugrel group (HR; 1.10; 95% CI, 0.81-1.50;P = .54). Conclusions and Relevance Among patients presenting with ACS who were treated with PCI, the incidence of the primary composite end point occurred less frequently for patients who received prasugrel compared with those who received ticagrelor. The incidence of bleeding events was comparable between the 2 groups. These results suggest that, for patients presenting with ACS who undergo PCI, a prasugrel-based strategy is superior to a ticagrelor-based strategy. However, because these observations are based on a postrandomization subgroup, these findings should be regarded as hypothesis generating and dedicated randomized clinical trials may be warranted to confirm these findings. Trial Registration ClinicalTrials.gov Identifier:NCT01944800

Background: The comparative efficacy and safety of ticagrelor and prasugrel in patients with acute coronary syndrome undergoing complex percutaneous coronary intervention (PCI) has not been defined. Methods: This post hoc analysis included all patients with acute coronary syndrome treated with PCI and randomized to either ticagrelor or prasugrel in the ISAR-REACT 5 trial (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment). Complex PCI was defined as at least one of the following: multivessel PCI, ≥3 stents implanted, ≥3 lesions treated, and total stented length >60 mm. The primary efficacy end point was the composite of all-cause death, myocardial infarction, or stroke; the safety end point was Bleeding Academic Research Consortium types 3 to 5 bleeding. Outcomes were assessed out to 12 months after randomization. Results: Among the 3377 patients treated with PCI in the ISAR-REACT 5 trial, 1429 underwent complex PCI (ticagrelor, N=696 and prasugrel, N=733) and 1948 underwent noncomplex PCI (ticagrelor, N=980 and prasugrel, N=968). There was no interaction between PCI complexity, assignment to either ticagrelor or prasugrel, and the primary efficacy or safety end points ( P for interaction: ≥0.13). In the complex PCI group, the primary efficacy end point (11.0% versus 9.2%, hazard ratio: 1.19 [0.85–1.66], P =0.303) and the safety end point (5.2% versus 6.1%, hazard ratio: 0.83 [0.53–1.31], P =0.419) were not statistically different in patients receiving either ticagrelor or prasugrel. In the noncomplex PCI group, the primary efficacy end point occurred more frequently in patients assigned to ticagrelor as compared to prasugrel (8.9% versus 5.5%, hazard ratio: 1.66 [1.18–2.34], P =0.004) without significant difference in terms of the safety end point (5.4% versus 4.1%, hazard ratio: 1.41 [0.92–2.17], P =0.110). Conclusions: In patients with acute coronary syndrome, PCI complexity does not influence the comparative efficacy and safety of ticagrelor and prasugrel. The observed comparable performance of ticagrelor and prasugrel in patients with acute coronary syndrome undergoing complex PCI requires further confirmation. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01944800.

Background The relative merits of ticagrelor as compared with prasugrel in patients with acute coronary syndromes for whom invasive evaluation is planned are uncertain. Methods In this mul...

AIMS: Clopidogrel is the P2Y12 inhibitor of choice in patients who undergo PCI and have an indication for oral anticoagulation (OAC). Prediction of the bleeding risk is of major interest in this population. The aim of this analysis was to investigate whether an enhanced platelet inhibition by clopidogrel measured by platelet function testing (PFT) with the Multiplate analyzer is associated with an increased bleeding risk in patients on triple antithrombotic therapy.METHODS AND RESULTS: This investigation was performed in a cohort of 524 patients from the randomized ISAR TRIPLE trial and 458 (87.4%) had PFT results available in the first 24 hours after PCI. Patients belonging to the lowest quintile according to PFT were considered as enhanced responders to clopidogrel. The primary endpoint was major bleeding according to TIMI criteria at 9 months. The median of ADP-induced platelet aggregation in the whole population was 163 AU*min [107-241]. Patients in the lowest quintile had values below 93 AU*min. These enhanced responders (92 patients) had a significantly higher risk of TIMI Major Bleeding (hazard ratio [HR]: 3.13, [95% confidence interval: 1.38-7.09], p=0.01) and overall mortality (HR: 3.42, [1.55-7.52], p=0.004) compared with the remaining patients (366 patients). No significant difference was observed for the secondary combined ischemic endpoint (HR: 1.27, [0.47-3.47], p=0.64).CONCLUSIONS: Enhanced platelet inhibition delivered by clopidogrel is associated with an increased risk for major bleeding and death in patients on OAC that undergo PCI. These results support the use of PFT to identify patients with an increased risk for bleeding.

Staphylococcus aureus is a major cause of bovine mastitis, commonly leading to long-lasting, persistent and recurrent infections. Thereby, S. aureus constantly refines and permanently adapts to the bovine udder environment. In this work, we followed S. aureus within-host adaptation over the course of three months in a naturally infected dairy cattle with chronic, subclinical mastitis. Whole genome sequence analysis revealed a complete replacement of the initial predominant variant by another isogenic variant. We report for the first time within-host evolution towards a sigma factor SigB-deficient pathotype in S. aureus bovine mastitis, associated with a single nucleotide polymorphism in rsbU (G368A → G122D), a contributor to SigB-functionality. The emerged SigB-deficient pathotype exhibits a substantial shift to new phenotypic traits comprising strong proteolytic activity and poly-N-acetylglucosamine (PNAG)-based biofilm production. This possibly unlocks new nutritional resources and promotes immune evasion, presumably facilitating extracellular persistence within the host. Moreover, we observed an adaptation towards attenuated virulence using a mouse infection model. This study extends the role of sigma factor SigB in S. aureus pathogenesis, so far described to be required for intracellular persistence during chronic infections. Our findings suggest that S. aureus SigB-deficiency is an alternative mechanism for persistence and underpin the clinical relevance of staphylococcal SigB-deficient variants which are consistently isolated during human chronic infections.

Despite dual antiplatelet therapy patients undergoing percutaneous coronary intervention (PCI) continue to experience periprocedural ischemic events. In addition, all currently used antithrombotic drugs increase the bleeding risk. Thus, there is an unmet clinical need for antithrombotic strategies with improved efficacy and no increase in bleeding. Revacept is a novel, lesion-directed antithrombotic drug that does not interfere with the function of circulating platelets. This dimeric fusion protein of the extracellular domain of glycoprotein VI (the major platelet collagen receptor) and the human Fc-fragment inhibits collagen-mediated platelet adhesion and subsequent aggregation at the site of vascular injury. The randomized, double-blinded, phase II ISAR-PLASTER trial is based on extensive preclinical evaluation of Revacept and a favorable first-in-man trial. A total of 332 patients with stable coronary artery disease undergoing elective PCI will be randomized to either Revacept 160 mg, Revacept 80 mg, or placebo administered as single intravenous infusion directly before the intervention, on top of standard dual antiplatelet therapy and either heparin or bivalirudin, based on local practice and current guidelines. The primary endpoint is the composite of death or myocardial injury (defined as increase in high sensitivity troponin T ≥ 5 times the upper limit of normal) at 48 hours. The safety endpoint is bleeding of class 2 or higher according to the Bleeding Academic Research Consortium at 30 days. This phase II randomized, double blind trial will assess for the first time the efficacy and safety of Revacept—a lesion-directed inhibitor of platelet adhesion—in patients undergoing elective PCI.

AimA common genetic variant at the GUCY1A3 coronary artery disease locus has been shown to influence platelet aggregation. The risk of ischaemic events including stent thrombosis varies with the efficacy of aspirin to inhibit platelet reactivity. This study sought to investigate whether homozygous GUCY1A3 (rs7692387) risk allele carriers display higher on-aspirin platelet reactivity and risk of ischaemic events early after coronary intervention.Methods and resultsThe association of GUCY1A3 genotype and on-aspirin platelet reactivity was analysed in the genetics substudy of the ISAR-ASPI registry (n = 1678) using impedance aggregometry. The clinical outcome cardiovascular death or stent thrombosis within 30 days after stenting was investigated in a meta-analysis of substudies of the ISAR-ASPI registry, the PLATO trial (n = 3236), and the Utrecht Coronary Biobank (n = 1003) comprising a total 5917 patients. Homozygous GUCY1A3 risk allele carriers (GG) displayed increased on-aspirin platelet reactivity compared with non-risk allele (AA/AG) carriers [150 (interquartile range 91–209) vs. 134 (85–194) AU⋅min, P 203 AU⋅min; 29.5 vs. 24.2%, P = 0.02). Homozygous risk allele carriers were also at higher risk for cardiovascular death or stent thrombosis (hazard ratio 1.70, 95% confidence interval 1.08–2.68; P = 0.02). Bleeding risk was not altered.ConclusionWe conclude that homozygous GUCY1A3 risk allele carriers are at increased risk of cardiovascular death or stent thrombosis within 30 days after coronary stenting, likely due to higher on-aspirin platelet reactivity. Whether GUCY1A3 genotype helps to tailor antiplatelet treatment remains to be investigated.

BACKGROUND Whether there are sex differences in the outcome of patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI) remains controversial. We undertook this study to assess whether there are sex-related differences in the long-term mortality in a large series of patients with CAD after PCI. METHODS The study included 18,334 patients (4735 women and 13,599 men) with CAD treated with PCI. Propensity matching was performed to obtain a group of patients (3000 women and 3000 men) matched for all characteristics available in database. The primary outcome was a composite of cardiac mortality, myocardial infarction or stroke at 3 years of follow-up. RESULTS The primary outcome occurred in 660 women and 1440 men (Kaplan-Meier [KM] estimates, 15.2% in women and 11.6% in men, unadjusted hazard ratio [HR] = 1.35, 95% confidence interval [CI] 1.24 to 1.49; P

Background: New-generation drug-eluting stents offer the potential for enhanced late outcomes in comparison with early generation drug-eluting stents. However, assessment of extended long-term outcomes for these devices is lacking, especially regarding the comparison between new-generation drug-eluting stents with biodegradable or permanent polymers. The aim of this study is to compare the efficacy and safety of biodegradable polymer-based sirolimus-eluting stents (BP-SES; Yukon Choice PC) versus permanent polymer-based everolimus-eluting stents (PP-EES; Xience) versus early generation permanent polymer-based sirolimus-eluting stents (PP-SES; Cypher) at 10-year follow-up. Methods: Overall, 2603 patients were randomized to treatment with BP-SES (n=1299), PP-EES (n=652), or PP-SES (n=652). The primary end point of this analysis was major adverse cardiac event, the composite of death, myocardial infarction, or target lesion revascularization. The main secondary end point of interest was definite/probable stent thrombosis. Follow-up at 10 years was available in 83% of the study patients. Results: The 10-year incidence of major adverse cardiac event (BP-SES 47.7% versus PP-EES 46.0% versus PP-SES 54.9%, P =0.003) and mortality (BP-SES 31.8% versus PP-EES 30.3% versus PP-SES 37.2%, P =0.02) was different among the groups. Definite/probable stent thrombosis was not significantly different among the groups (BP-SES 1.8% versus PP-EES 2.5% versus PP-SES 3.7%, P =0.09). Definite stent thrombosis was significantly different among the groups (BP-SES 1.1% versus PP-EES 0.8% versus PP-SES 2.4%, P =0.03). There were no significant differences between BP-SES and PP-EES. Conclusions: In this unique long-term outcome analysis, BP-SES and PP-EES showed comparable clinical outcomes out to 10 years. PP-SES had higher rates of major adverse cardiac events and definite stent thrombosis. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00598676.

AIM Sex-specific analyses of direct head-to-head comparisons between newer P2Y12 inhibitors are limited. This study was conducted to assess the efficacy and safety of ticagrelor versus prasugrel in women and men with acute coronary syndromes (ACS) planned for an invasive strategy. METHODS This pre-specified analysis of the ISAR-REACT 5 trial included 956 women and 3,062 men with ACS randomly assigned to either ticagrelor or prasugrel. The primary endpoint was the 12-month incidence of death, myocardial infarction, or stroke; the safety endpoint was the 12-month incidence of bleeding (type 3-5 according to the Bleeding Academic Research Consortium [BARC]). RESULTS The primary endpoint occurred in 42 women (8.9%) in the ticagrelor group and 39 women (8.3%) in the prasugrel group (hazard ratio [HR]=1.10, 95% confidence interval [CI] 0.71-1.70, P=0.657) and in 142 men (9.4%) in the ticagrelor group and 98 men (6.5%) in the prasugrel group (HR=1.47 [1.13-1.90], P=0.004; P for interaction [Pint]=0.275). BARC type 3-5 bleeding occurred in 36 women (9.7%) in the ticagrelor group and 34 women (9.7%) in the prasugrel group (HR=1.04 [0.65-1.67], P=0.856) and in 59 men in the ticagrelor group (4.4%) and 46 men (3.6%) in the prasugrel group (HR=1.24 [0.85-1.83], P=0.266; Pint=0.571). CONCLUSIONS Although there was no significant interaction between sex and treatment effect of study drugs, the superior efficacy of prasugrel was more evident among men. No difference in bleeding between the two study groups was seen for both women and men.

Importance The assessment of new antithrombotic agents with a favorable safety profile is clinically relevant. Objective To test the efficacy and safety of revacept, a novel, lesion-directed antithrombotic drug, acting as a competitive antagonist to platelet glycoprotein VI. Design, Setting, and Participants A phase 2 randomized clinical trial; patients were enrolled from 9 centers in Germany from November 20, 2017, to February 27, 2020; follow-up ended on March 27, 2020. The study included patients with stable ischemic heart disease (SIHD) undergoing elective percutaneous coronary intervention (PCI). Interventions Single intravenous infusion of revacept, 160 mg, revacept, 80 mg, or placebo prior to the start of PCI on top of standard antithrombotic therapy. Main Outcomes and Measures The primary end point was the composite of death or myocardial injury, defined as an increase in high-sensitivity cardiac troponin to at least 5 times the upper limit of normal within 48 hours from randomization. The safety end point was bleeding type 2 to 5 according to the Bleeding Academic Research Consortium criteria at 30 days. Results Of 334 participants (median age, 67.4 years; interquartile range, 60-75.1 years; 253 men [75.7%]; and 330 White participants [98.8%]), 120 were allocated to receive the 160-mg dose of revacept, 121 were allocated to receive the 80-mg dose, and 93 received placebo. The primary end point showed no significant differences between the revacept and placebo groups: 24.4%, 25.0%, and 23.3% in the revacept, 160 mg, revacept, 80 mg, and placebo groups, respectively (P = .98). The high dose of revacept was associated with a small but significant reduction of high-concentration collagen-induced platelet aggregation, with a median 26.5 AU × min (interquartile range, 0.5-62.2 AU × min) in the revacept, 160 mg, group; 43.5 AU × min (interquartile range, 22.8-99.5 AU × min) in the revacept, 80 mg, group; and 41.0 AU × min (interquartile range, 31.2-101.0 AU × min) in the placebo group (P = .02), while adenosine 5′-diphosphate–induced aggregation was not affected. Revacept did not increase Bleeding Academic Research Consortium type 2 or higher bleeding at 30 days compared with placebo: 5.0%, 5.9%, and 8.6% in the revacept, 160 mg, revacept, 80 mg, and placebo groups, respectively (P = .36). Conclusions and Relevance Revacept did not reduce myocardial injury in patients with stable ischemic heart disease undergoing percutaneous coronary intervention. There were few bleeding events and no significant differences between treatment arms. Trial Registration ClinicalTrials.gov Identifier:NCT03312855

A major determinant of β-lactam resistance in methicillin-resistant Staphylococcus aureus (MRSA) is the drug insensitive transpeptidase, PBP2a, encoded by mecA. Full expression of the resistance phenotype requires auxiliary factors. Two such factors, aux iliary factor A (auxA, SAUSA300_0980) and B (auxB, SAUSA300_1003), were identified in a screen against mutants with increased susceptibility to β-lactams in the MRSA strain, JE2. auxA and auxB encode transmembrane proteins, with AuxA predicted to be a transporter. Inactivation of auxA or auxB enhanced β-lactam susceptibility in community-, hospital- and livestock-associated MRSA strains without affecting PBP2a expression, peptidoglycan cross-linking or wall teichoic acid synthesis. Both mutants displayed increased susceptibility to inhibitors of lipoteichoic acid (LTA) synthesis and alanylation pathways and released LTA even in the absence of β-lactams. The β-lactam susceptibility of the aux mutants was suppressed by mutations inactivating gdpP, which was previously found to allow growth of mutants lacking the lipoteichoic synthase enzyme, LtaS. Using the Galleria mellonella infection model, enhanced survival of larvae inoculated with either auxA or auxB mutants was observed compared with the wild-type strain following treatment with amoxicillin. These results indicate that AuxA and AuxB are central for LTA stability and potential inhibitors can be tools to re-sensitize MRSA strains to β-lactams and combat MRSA infections.

Introduction Reticulated or immature Platelets are pro-thrombotic RNA-rich young platelets, which have been reported to correlate with adverse events in several pathological settings including coronary artery disease. However, the predictive value of this subgroup of platelets in patients with acute coronary syndrome treated with the potent novel P2Y12 inhibitors prasugrel or ticagrelor has not been investigated yet. Moreover, their role as predictors of major bleeding is unclear. Purpose The primary aim of this prespecified reticulated platelet ISAR-REACT-5 substudy was to evaluate the immature platelet fraction (IPF%) in peripheral blood as a predictor of the composite primary endpoint consisting of death, myocardial infarction, or stroke at one year after randomization in patients with acute coronary syndrome. Methods IPF was assessed in the first 24h after randomization using a fully automated system and correlated to the incidence of the primary endpoint. All patients with available IPF values were included. The Sysmex system uses two fluorescent dyes to stain platelet RNA and a computer algorithm (Sysmex IPF Master) discriminates immature from mature platelets by the intensity of forward scattered light and fluorescence. The immature platelet fraction is displayed as percentage of the total optical platelet count (IPF%). Results IPF values within the first 24h after randomization were available in a total of 506 randomized patients. Baseline characteristics and IPF (median [IQR]) values did not differ between the 2 study groups (IPF: prasugrel 3.9% [2.7–5.8] ticagrelor 3.4% [2.5–5.6] p=0.56). Significantly higher IPF values were observed in patients reaching the primary endpoint (n=55 of 506) independent from the study group (p for interaction= 0.28). ROC-curve analysis revealed a cut-of value of IPF 3.6% for the prediction of death, myocardial infarction or stroke with a Hazard ratio (HR) according to cox-regression analysis of 1.98 (95% CI, 1.15–3.44), P=0.01 (Figure 1A). Interestingly, we also detected a trend for higher major bleedings (BARC 3–5) in patients with elevated IPF values above IPF>4.8% according to ROC-curve analysis (Figure 1B). Conclusion IPF was significantly associated with the primary endpoint in the ISAR-REACT 5 substudy independent from the treatment group and therefore is a promising novel biomarker for the prediction of adverse cardiovascular events in patients with acute coronary syndrome. Figure 1 Funding Acknowledgement Type of funding source: None

Introduction The recently published randomized multicenter open label ISAR REACT 5 trial showed that prasugrel was superior to ticagrelor with respect to the composite primary end point of death, myocardial infarction, or stroke at one year after randomization in patients with acute coronary syndrome with planned invasive evaluation. The reasons for this finding are speculative. Purpose The aim of this prespecified platelet aggregation substudy was to assess platelet aggregation induced by adenosine-diphosphate (ADP) in patients who received prasugrel or ticagrelor treatment and underwent PCI. Methods We assessed all patients who underwent PCI and who had valid ADP-induced platelet aggregation values at hospital admission and at 2–24 hours after administration of prasugrel or ticagrelor loading dose followed by maintenance dose. ADP-induced platelet aggregation values were measured using the Mulitplate Analyzer®. Patients were recruited in the German Heart Center, Munich, Germany or in Klinikum rechts der Isar, Munich, Germany, Technical University of Munich. Results A total of 608 patients were analyzed. Patients in the prasugrel group were slightly but significantly older than patients in the ticagrelor group (66,5 years versus 64,6 years, P=0,048). The remaining baseline characteristics did not significantly differ between the two treatment groups. ADP-induced platelet aggregation (median [IQR]) at baseline did not differ between prasgurel- and ticagrelor treated patients (809 [556; 1057] AU x min versus 797 [534–1095] AU x min. At 2–24 hours after study drug administration ADP-induced platelet aggregation was significantly lower in patients who had received prasugrel in comparison to ticagrelor (105 [57–176] AU x min versus 138 [77–207] AU x min (Figure 1). Conclusion ADP-induced platelet aggregation was significantly lower in patients who received prasugrel in comparison to patients who received ticagrelor, which could have influenced patients' outcome in the ISAR-REACT 5 trial. Figure 1 Funding Acknowledgement Type of funding source: None