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Abstract Background Transanal endoscopic microsurgery as a local therapy option for rectal neoplasms is a tissue-sparing technique that protects the anal sphincter. The present retrospective analysis reports the course of observation after local excision of adenomas and T1 low-risk carcinomas using transanal endoscopic microsurgery. Methods In a retrospective analysis we examined data on 279 patients for local recurrence. A total of 144 patients had a rectal adenoma (n = 103) or a R0 resection of low-risk T1 carcinomas (n = 41). In this collective, we also examined parameters concerning perioperative management, complications, intraoperative blood loss and duration of hospital stay. Results Patients with adenoma were on average 64.9 (range 37 to 90) years old; 83.5% of the adenomas were located 3 to 11 cm from the anocutaneous line. In adenoma patients the recurrence rate was 2.9% for an observation period of 21.8 months. The postoperative course was without any complications in 98.1% of patients. Patients with T1 low-risk carcinoma were 64.6 (range 30 to 89) years old. In all cases, an R0 resection could be performed. The recurrence rate was 9.8% for an observation period of 34.4 months. In this group the postoperative course was free of complications in 97.6% of patients. Conclusions The high efficacy of transanal endoscopic microsurgery ensures minimally invasive treatment of adenomas and low-risk T1 carcinomas with low complication rates and a low rate of therapeutic failure.

Objectives: We investigated whether the loss of function CYP2C19 681G>A *2 polymorphism is associated with high (>14%) residual platelet aggregation (RPA) on clopidogrel and whether high on-clopidogrel RPA impacts clinical outcome after elective coronary stent placement.Background: The cytochrome P450 (CYP)-dependent conversion of clopidogrel to its active metabolite may contribute to the variability in antiplatelet effect of clopidogrel.Methods: The study included 797 consecutive patients undergoing percutaneous coronary intervention, who were followed-up for 1 year. Adenosine-diphosphate-induced (5 mumol/l) RPA was assessed after a 600-mg loading dose and after the first 75-mg maintenance dose of clopidogrel before discharge. CYP2C19 genotype was analyzed by real-time polymerase chain reaction.Results: Of the patients included, 552 (69.3%) were CYP2C19 wild-type homozygotes (*1/*1) and 245 (30.7%) carried at least one *2 allele. Residual platelet aggregation at baseline did not differ significantly between genotypes. On clopidogrel, RPA was significantly (p < 0.001) higher in *2 carriers than in wild-type homozygotes (23.0% [interquartile range (IQR) 8.0% to 38.0%] vs. 11.0% [IQR 3.0% to 28.0%] after loading; 11.0% [IQR 5.0% to 22.0%] vs. 7.0% [IQR 3.0% to 14.0%] at pre-discharge). Between *2 carriers and wild-type homozygotes, we found significant (p < 0.001) differences in the proportion of patients with RPA >14%, both after loading (62.4% vs. 43.4%) and at pre-discharge (41.3% vs. 22.5%). Residual platelet aggregation >14% at pre-discharge incurred a 3.0-fold increase (95% confidence interval 1.4 to 6.8; p = 0.004) in the 1-year incidence of death and myocardial infarction.Conclusions: Patients carrying at least one CYP2C19*2 allele are more prone to high-on clopidogrel platelet reactivity, which is associated with poor clinical outcome after coronary stent placement (Effect of Clopidogrel Loading and Risk of PCI [EXCELSIOR]; NCT00457236). [ABSTRACT FROM AUTHOR]

Background: Inclisiran is a small interfering RNA agent to lower low-density lipoprotein cholesterol., Objectives: The purpose of this study was to provide reliable evidence to date on the long-term safety profile of inclisiran., Methods: This post hoc analysis comprised patients treated with 300 mg inclisiran sodium or placebo in the completed (ORION-1, -3, -5, -9, -10, and -11) and ongoing (ORION-8) trials. Exposure-adjusted incidence rates and Kaplan-Meier estimates of cumulative incidence of reported treatment-emergent adverse events (TEAE), abnormal laboratory measurements, and incidence of antidrug antibodies were analyzed., Results: This analysis included 3,576 patients treated with inclisiran for up to 6 years and 1,968 patients treated with placebo for up to 1.5 years, with 9,982.1 and 2,647.7 patient-years of exposure, respectively. Baseline characteristics were balanced between groups. Kaplan-Meier analyses showed that TEAEs that were serious or led to discontinuation; hepatic, muscle, and kidney events; incident diabetes; and elevations of creatine kinase or creatinine accrued at a comparable rate between groups for up to 1.5 years, with similar trends continuing for inclisiran beyond this period. Numerically fewer major cardiovascular events reported as TEAEs occurred with inclisiran during this period. Treatment-induced antidrug antibodies were uncommon with inclisiran (4.6%), with few of these persistent (1.4%) and not associated with greater incidence of TEAEs leading to study drug discontinuation or serious TEAEs., Conclusions: Long-term treatment with inclisiran was well tolerated in a diverse population, without new safety signals, supporting the safety of inclisiran in patients with dyslipidemia., Competing Interests: Funding Support and Author Disclosures This study was sponsored by Novartis Pharma AG. Dr Wright has received advisory board fees from Boehringer Ingelheim; and has received past fees for consulting on lipid issues with The Medicines Company. Dr Koenig has received consulting fees and lecture fees from AstraZeneca, Novartis, and Amgen; has received consulting fees from Pfizer, The Medicines Company, Novartis, DalCor Pharmaceuticals, Kowa, Corvidia Therapeutics, Esperion, Genentech, OMEICOS, Novo Nordisk, LIB Therapeutics, Daiichi-Sankyo, New Amsterdam Pharma, and TenSixteen Bio; has received lecture fees from Berlin-Chemie, Bristol Myers Squibb, and Sanofi; and has received grant support and provision of reagents from Singulex, Abbott, Roche Diagnostics, and Dr Beckmann Pharma. Dr Landmesser has received lecture fees and advisory fees from AstraZeneca, Boehringer Ingelheim, Sanofi, Berlin-Chemie, and Abbott; has received advisory fees from The Medicines Company; and has received grant support, lecture fees, and advisory fees from Amgen, Bayer, and Novartis. Dr Leiter has received grant support paid to his institution and advisory board fees and fees for CME from Amgen and Novartis; has received fees for serving on a steering committee and advisory board fees from Esperion; has received grant support paid to his institution and fees for serving on a steering committee from Kowa, The Medicines Company, and Novartis; and has received advisory board fees and fees for CME from Amarin, AstraZeneca, HLS, Merck, Pfizer, and Sanofi. Dr Raal has received advisory board fees and lecture fees from Amgen, Sanofi, Regeneron Pharmaceuticals, Novartis, and LIB Therapeutics. Dr Schwartz has received research support paid to his institution from AstraZeneca, Resverlogix, Sanofi, Silence Therapeutics, and The Medicines Company; and has a patent (62/806313) on a method for reducing cardiovascular risk assigned in full to the University of Colorado. Drs Lesogor, Maheux, Stratz, Zang, and Ray were employed by Novartis at the time of analysis. Dr Ray has received support from the National Institute for Health and Care Research (NIHR) Imperial Biomedical Research Centre; his institution (Imperial College London) receives support from the National Institute for Health and Care Research Applied Research Collaboration Northwest London; has received lecture fees from Aegerion Pharmaceuticals, Kowa, Cipla, Algorithm, and Zuelling Pharma; has received grant support paid to his institution, lecture fees, and advisory board fees from Amgen, Regeneron Pharmaceuticals/Sanofi, and Pfizer; has received lecture fees and fees for serving on steering committees for trials from AstraZeneca and Eli Lilly; has received fees for serving on steering committees for trials from Cerenis Therapeutics, The Medicines Company, and Esperion; has received advisory board fees from Akcea Therapeutics, Novartis, Silence Therapeutics, Bayer, and Daiichi-Sankyo; has received lecture fees and advisory board fees from Takeda, Boehringer Ingelheim, and Dr Reddy’s Laboratories; has received grant support and advisory board fees from Merck Sharp and Dohme; has received fees for serving on a clinical events adjudication committee from AbbVie; and has received fees for serving as principal investigator for a trial from Resverlogix., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Inclisiran is a small interfering RNA molecule that reduces low-density lipoprotein cholesterol (LDL-C) by inhibition of proprotein convertase subtilisin/kexin type 9. This subcutaneous, twice-yearly administered agent has been shown to effectively and safely lower LDL-C in adult patients with established atherosclerotic cardiovascular disease, adults at high risk for atherosclerotic cardiovascular disease, as well as in adults with heterozygous familial hypercholesterolaemia. With the current, limited treatment options available to reach treatment goals in children with severe heterozygous familial hypercholesterolaemia, homozygous familial hypercholesterolaemia, or statin intolerance, inclisiran could be a valuable new therapeutic option., Objectives: The objective of these ongoing studies is to investigate the efficacy, safety, and tolerability of inclisiran in adolescents diagnosed with homozygous familial hypercholesterolaemia (ORION-13) or heterozygous familial hypercholesterolaemia (ORION-16)., Study Design: ORION-13 and ORION-16 are both two-part (1-year double-blind inclisiran vs. placebo/1 year open-label inclisiran) multicentre trials including adolescents aged 12 to &lt;18 years diagnosed with familial hypercholesterolaemia. ORION-13 will include ∼12 participants diagnosed with homozygous familial hypercholesterolaemia and ORION-16 will include ∼150 participants diagnosed with heterozygous familial hypercholesteroleamia. The primary endpoint is the percentage change in LDL-C from baseline to Day 330. Secondary efficacy and safety endpoints include changes in other lipid parameters and treatment-emergent adverse events as well as laboratory parameters and vital signs. Exploratory endpoints include individual responsiveness of the participants and change in LDL-C according to the type of underlying causal mutation., Clinical Trial Registration: https://www.clinicaltrials.gov/. Unique identifier: NCT04659863 (ORION-13) and NCT04652726 (ORION-16)., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2022. For permissions, please email: journals.permissions@oup.com.)

Background: Sepsis is associated with high platelet turnover and elevated levels of immature platelets. Changes in the platelet transcriptome and the specific impact of immature platelets on the platelet transcriptome remain unclear. Thus, this study sought to address whether and how elevated levels of immature platelets affect the platelet transcriptome in patients with sepsis., Methods: Blood samples were obtained from patients with sepsis requiring vasopressor therapy (n = 8) and from a control group of patients with stable coronary artery disease and otherwise similar demographic characteristics (n = 8). Immature platelet fraction (IPF) was determined on a Sysmex XE 2100 analyser and platelet function was tested by impedance aggregometry. RNA from leukocyte-depleted platelets was used for transcriptome analysis by Next Generation Sequencing integrating the use of unique molecular identifiers., Results: IPF (median [interquartile range]) was significantly elevated in sepsis patients (6.4 [5.3-8.7] % vs. 3.6 [2.6-4.6] %, p = 0.005). Platelet function testing revealed no differences in adenosine diphosphate- or thrombin receptor activating peptide-induced platelet aggregation between control and sepsis patients. Putative circular RNA transcripts were decreased in platelets from septic patients. Leukocyte contamination defined by CD45 abundance levels in RNA-sequencing was absent in both groups. Principal component analysis of transcripts showed only partial overlap of clustering with IPF levels. RNA sequencing showed up-regulation of 524 and down-regulation of 118 genes in platelets from sepsis patients compared to controls. Upregulated genes were mostly related to catabolic processes and protein translation. Comparison to published platelet transcriptomes showed a large overlap of changes observed in sepsis and COVID-19 but not with reticulated platelets from healthy donors., Conclusions: Patients with sepsis appear to have a less degraded platelet transcriptome as indicated by increased levels of immature platelets and decreased levels of putative circular RNA transcripts. The present data suggests that increased protein translation is a characteristic mechanism of systemic inflammation., Competing Interests: The authors have declared that no competing interests exist.

There are clinical scenarios where the balance between the risk of ischemic and bleeding events leads to the clinical decision to reverse the antiplatelet effect of P2Y 12 receptor inhibitors. These scenarios comprise emergency situations such as active severe bleeding, urgent procedures with presumed high bleeding risk, or major trauma with (anticipated) bleeding. Supplementation of platelets has been investigated in ex vivo as well as in in vivo studies. These studies indicate that the inhibition of adenosine diphosphate-induced aggregation by the irreversibly binding thienopyridine derivatives clopidogrel and prasugrel can be reversed by administration of platelet concentrates. Supplementation of platelets in patients on prasugrel is more effective if this can be transfused > 6 hours after last dosing. Studies on the reversal effect obtained by administration of platelet concentrates in patients on ticagrelor show conflicting results. Experimental data suggest that administration of serum albumin might increase the reversal effect. A monoclonal antibody fragment (PB2452) for neutralizing ticagrelor is currently in clinical development. A recently published first in man study shows that reversal of platelet inhibition occurs within 5 minutes after start of administration and the effect is maintained for 20 to 24 hours after a 16-hour infusion which is by far the most effective approach for reversal of ticagrelor., Competing Interests: D.T. reports lecture fees from Amgen, AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Pfizer, and Sanofi and fees for advisory board activities from Bayer, Boehringer Ingelheim, and Daiichi Sankyo. D.A. reports lecture fees from Astra Zeneca, Bayer, Boehringer Ingelheim, Pfizer, and MSD Pharma. K.S. reports personal fees from Bayer. D.S. reports grants and personal fees from Sanofi Aventis, Roche Diagnostics, and Daiichi Sankyo; personal fees from Bayer, Pfizer, and Haemonetics S.A. All the other authors have no conflict of interest to declare., (Georg Thieme Verlag KG Stuttgart · New York.)

Aims: We sought to evaluate haemodynamic prosthetic valve performance in patients with early leaflet thrombosis (LT) after transcatheter aortic valve implantation (TAVI)., Method and Results: In this retrospective observational study, 59 patients with LT underwent clinical and echocardiographic follow-up. During a median follow-up of 383 days 41 patients received antiplatelet therapy (APT-group) and 18 patients oral anticoagulation due to atrial fibrillation (AC-group). The mean pressure gradient (MPG) at baseline did not differ between groups (P = 0.875). During follow-up, MPG increased from 11.0 (9.0; 14.5) to 13.0 mmHg (10.0; 18.0)&#95; in the APT-group (P = 0.010) but remained unchanged in the AC-group (P = 0.297) resulting in a significantly higher MPG in patients on antiplatelet therapy (P = 0.024). Similarly, change of MPG per year was significantly higher in the APT-group [1.4 (- 0.9; 7.0) vs. - 0.6 (- 2.5; 1.1), P = 0.014]. Seven (17.1%) patients in the APT-group and two(11.1%) patients in the AC-group developed MPGs of at least 20 mmHg (P = 0.558). Three patients (7.3%) in the APT- and none in the AC-group developed symptoms of obstructive thrombosis (P = 0.239). In our adjusted analysis, only lack of anticoagulation was significantly associated with change in gradients during follow-up (P = 0.012)., Conclusions: In patients with LT, antiplatelet-, but not anticoagulant therapy, was associated with significant increases in MPG, which may lead to symptomatic obstructive valve thrombosis.

Reticulated platelets reflect the rate of platelet turnover and represent the youngest circulating platelets in peripheral blood. Reticulated platelets contain residual ribonucleic acid (RNA) from megakaryocytes which is lost in a time-dependent manner and can be transcribed into proteins even in the absence of a nucleus. An increased proportion of reticulated platelets is associated with higher platelet reactivity, cardiovascular events and mortality. At present, a fully automated assay system (SYSMEX haematology analyser) is available for analysis. This method, however, is not suitable for extended laboratory investigations like subsequent cell sorting. Flow cytometry analysis after staining with thiazole orange (TO) is frequently used in such settings despite several limitations. Here, we describe a new assay for determination of reticulated platelets by flow cytometry using the nucleic acid staining dye SYTO 13 and compare it with SYSMEX and TO staining as current standards. A significant correlation between immature platelet fraction (IPF) determined by SYSMEX XE-2100 analyser and results obtained with the SYTO 13-based assay was observed ( r  = 0.668, p  < 0.001) which was stable during a reasonable time period. In contrast, the correlation between TO staining and IPF was weaker ( r  = 0.478, p  = 0.029) and lost after 90 minutes of staining. SYTO 13 staining of platelets enabled sorting of RNAlow and RNArich platelets which was confirmed by RNA quantification of sorted platelets. Except for fixation of platelets, sorting of these platelet sub-populations was stable under various experimental settings. In summary, determination of reticulated platelets with the new SYTO 13 assay offers distinct technical advantages enabling further laboratory processing., Competing Interests: Miss Hille reports grants from PharmCompNet Baden-Württemberg: Kompetenznetzwerk Pharmakologie Baden-Württemberg, grants from University Heart Center Freiburg - Bad Krozingen, during the conduct of the study.Dr. Trenk reports grants fromPharmCompNet Baden-Württemberg:Kompetenznetzwerk Pharmakologie Baden-Württemberg during the conduct of the study; personal fees from Amgen, AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Pfizer and Sanofi, outside the submitted work.Dr. Cederqvist, Dr. Hromek, Dr. Stratz and Dr. Nührenberg report no conflicts of interest., (Georg Thieme Verlag KG Stuttgart · New York.)

Objectives: To assess the impact of on-clopidogrel platelet reactivity (PR) on HALT, the authors prospectively tested whether patients with below-median on-clopidogrel PR have a lower incidence of HALT compared with those with above-median on-clopidogrel PR., Background: It is unclear whether the apparent ineffectiveness of clopidogrel in preventing hypoattenuated leaflet thickening (HALT) after transcatheter aortic valve replacement (TAVR) questions the concept of P2Y 12 inhibition after TAVR or is a consequence of an inadequate response to clopidogrel in elderly patients with severe aortic stenosis., Methods: Patients were either on long-term dual antiplatelet therapy with clopidogrel and acetylsalicylic acid or were given bolus doses of both drugs the day before TAVR. Adenosine diphosphate (ADP)-induced multielectrode impedance aggregometry was performed before TAVR. After TAVR, clopidogrel was continued in all patients. Computed tomographic angiography was performed to detect HALT., Results: Of 331 patients enrolled, computed tomographic angiography was performed in 200 at 5 days (interquartile range: 4 to 6 days). Among patients with below-median ADP-induced PR (<180 AU · min), 16 were diagnosed with HALT, whereas 20 patients with above-median PR were diagnosed with HALT (p = 0.58). Among patients with high on-clopidogrel PR (>468 AU · min; n = 29), 7 (24%) displayed HALT, compared with 19 (17%) with ADP-induced PR ≤468 AU · min (p = 0.43). Consistently, ADP-induced PR as a continuous variable was not significantly associated with HALT (p = 0.75). Oral anticoagulation was associated with reduced rates of HALT (odds ratio: 0.41; 95% CI: 0.18 to 0.96; p = 0.04)., Conclusions: On-clopidogrel ADP-induced PR was not significantly associated with the occurrence of HALT. In contrast, oral anticoagulation was associated with reduced rates of HALT., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Current guidelines recommend as treatment option in patients on oral anticoagulation (OAC) undergoing percutaneous coronary intervention (PCI) an antiplatelet monotherapy with clopidogrel if there is an increased risk for bleeding. However, retrospective data suggested a potential interaction of clopidogrel and the vitamin K antagonist (VKA) phenprocoumon leading to a diminished antiplatelet effect. This would increase the ischemic risk of patients treated with this combination. Thus, this prospective study sought to evaluate the pharmacodynamic effect of clopidogrel monotherapy in patients on phenprocoumon undergoing PCI and assessed clinical outcomes. This study enrolled 100 patients on aspirin plus clopidogrel (DAPT-cohort, without indication for VKA) and 100 patients on clopidogrel monotherapy plus phenprocoumon (OAC-cohort) undergoing elective PCI. Platelet reactivity was assessed by impedance aggregometry on day 1 following PCI. Ischemic (death, stroke, or myocardial infarction) and bleeding (BARC 2-5) events within 12 months were compared in a propensity score adjusted model. Platelet reactivity was not different in the OAC- and DAPT-cohort (187 [127-242] vs. 167 [126-218] AU×min; p  = 0.23). Overall, 17 ischemic and 34 bleeding events were recorded during follow-up. The OAC-cohort showed a nonsignificant trend to an 80% higher incidence for ischemic and bleeding events in unadjusted analyses, which disappeared following adjustment (ischemic events HR 1.07, 95%-CI 0.32-3.59, p  = 0.91; bleeding events HR 1.25, 95%-CI 0.46-3.40, p  = 0.67). Following PCI, the pharmacodynamic effect of a clopidogrel monotherapy together with phenprocoumon is similar as compared to DAPT without a VKA, and not associated with an increased risk for ischemic events beyond the higher underlying baseline risk.

Background: Diabetes mellitus (DM) has been associated with increased platelet reactivity as well as increased levels of platelet RNAs in plasma. Here, we sought to evaluate whether the platelet transcriptome is altered in the presence of uncontrolled DM., Methods: Next-generation sequencing (NGS) was performed on platelet RNA for 5 patients with uncontrolled DM (HbA1c 9.0%) and 5 control patients (HbA1c 5.5%) with otherwise similar clinical characteristics. RNA was isolated from leucocyte-depleted platelet-rich plasma. Libraries of platelet RNAs were created separately for long RNAs after ribosomal depletion and for small RNAs from total RNA, followed by next-generation sequencing., Results: Platelets in both groups demonstrated RNA expression profiles characterized by absence of leukocyte-specific transcripts, high expression of well-known platelet transcripts, and in total 6,343 consistently detectable transcripts. Extensive statistical bioinformatic analysis yielded 12 genes with consistently differential expression at a lenient FDR < 0.1, thereof 8 protein-coding genes and 2 genes with known expression in platelets ( MACF1 and ITGB3BP) . Three of the four differentially expressed noncoding genes were YRNAs ( RNY1, RNY3, and RNY4 ) which were all downregulated in DM. 23 miRNAs were differentially expressed between the two groups. Of the 13 miRNAs with decreased expression in the diabetic group, 8 belonged to the DLK1-DIO3 gene region on chromosome 14q32.2., Conclusions: In this study, uncontrolled DM had a remote impact on different components of the platelet transcriptome. Increased expression of MACF1 , together with supporting predicted mRNA-miRNA interactions as well as reduced expression of RNYs in platelets, may reflect subclinical platelet activation in uncontrolled DM.

In patients at high risk for bleeding undergoing percutaneous coronary intervention (PCI) the use of bare-metal-stent (BMS) is considered an option that allows discontinuation of clopidogrel after 4 weeks. We sought to investigate the risk of early discontinuation of clopidogrel in patients with BMS as compared with a 6-month course of clopidogrel after DES in patients with or without high on-treatment platelet reactivity (HTPR). In 765 consecutive patients undergoing PCI after loading with clopidogrel 600 mg, HTPR was tested by optical aggregometry and defined as residual platelet reactivity > 14%. On top of aspirin 100 mg, patients received clopidogrel 75 mg for 4 weeks after BMS or 6 months after DES. The primary endpoint was all-cause mortality or myocardial infarction (MI) during 1 year. The 1-year incidence of death or MI was 3.5% with BMS (n = 484), 0.9% with DES and no HTPR (n = 211), and 7.1% with DES and HTPR (n = 70; p = 0.03). Landmark analyses for the first 6 months demonstrated that the risk of patients receiving BMS was similar as in patients receiving a DES with HTPR during this period (2.3 vs. 2.9%) but lowest in patients receiving a DES without HTPR (0.5%). The incidence of bleeding was similar in all three groups. These findings did not change after propensity score adjustment for stent type. After discontinuation of clopidogrel at 1 month, patients treated with BMS are at higher risk for death or MI than patients treated with a DES and sufficiently responding to clopidogrel planned for 6 months.ClinicalTrials.gov number NCT00457236.