Inclisiran-new hope in the management of lipid disorders?

Drugs reducing plasma concentrations of apolipoprotein-B (ApoB) containing lipoproteins have been demonstrated to reduce the risk of cardiovascular disease (CVD) in both primary and secondary prevention. Despite the demonstrated efficacy of statins and ezetimibe on low-density lipoprotein (LDL) concentration and long-term CVD risk, a large number of patients do not achieve their therapeutic goals. The introduction of monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9) protein was a milestone in the treatment of lipid disorders, as their administration leads to unprecedentedly low LDL-C concentrations. Inclisiran represents an entirely new mechanism of PSCK9 protein inhibition in hepatocytes, targeting the messenger RNA (mRNA) for PCSK9. Its administration is necessary only every 3-6 months, which is an essential advantage over statin and monoclonal antibody therapy. The infrequent administration regimen can increase the number of patients who maintain their therapeutic goals, especially in patients struggling to comply with daily or biweekly pharmacotherapy. Preclinical studies and Phase I and Phase II clinical trials of inclisiran have demonstrated its tolerability and efficacy in promoting long-term reduction of both PCSK9 protein and LDL-C. The efficacy and safety of inclisiran will continue to be assessed in ongoing and forthcoming trials on larger patient groups. If the results of these trials reflect previously published data, they will add further evidence that inclisiran might be a revolutionary new tool in the pharmacological management of plasma lipids. This review summarizes the currently available literature data on inclisiran with respect to its mechanism of action, effectiveness and safety as a lipid-lowering drug for CVD prevention

Risk-factors associated with extremely high cardiovascular risk of mid- and long-term mortality following myocardial infarction: An analysis of the Hyperlipidaemia Therapy in tERtiary Cardiological cEnTer (TERCET) Registry

Introduction: Risk-factor identification and risk stratification are prerequisites to the effective primary and secondary prevention of cardiovascular disease (CVD). Patients at the highest risk benefit the most from the intensive risk-factor reduction. However, high-risk patients’ group is heterogeneous, and it is increasingly recognised that there is an 'extreme-risk' category of patients who may require particularly close attention and intensive therapeutic approach. The aim of this study was to identify subgroups of patients at the highest risk of death following myocardial infarction (MI) that might be considered as those at extremely high CVD risk. Methods: We used data from 19,582 participants of the Hyperlipidaemia Therapy in tERtiary Cardiological cEnTer (TERCET) Registry (NCT03065543) of patients with ischaemic heart disease in Poland from 2006-present. Characteristics of 13,052 patients with chronic coronary syndromes (CCS) were compared with those of 4,295 patients with myocardial infarction (STEMI and 48 NSTEMI). Multivariable logistic regression with stepwise backward elimination was used to identify risk factors associated with mortality in the 12-36 months following the index hospitalisation. Results: The mortality rates were significantly higher in patients after MI than in patients with CCS. In the multivariable analysis, the risk factors most strongly associated with 12-month mortality in patients after MI were left ventricular ejection fraction (LVEF) lower than 35% (hazard ratio [HR] 3.83, 95% confidence interval [CI] 3.14-4.67), age >75 years (HR 1.91, 95%CI 1.55-2.35), multivessel coronary artery disease (HR 1.61, 95%CI 1.30-1.99), atrial fibrillation (HR 1.53, 95%CI 55 1.21-1.94) diabetes mellitus (HR 1.35, 95%CI 1.11-1.64) and increased LDL-C (HR per 1 mmol/l 56 1.09, 95%CI 1.01-1.19) or creatinine levels (HR per 10 µmol/L 1.04, 95% CI 1.04-1.05). The risk factors that influenced mortality after 24-36 months were consistent with those after 12 months, with additional low haemoglobin (20-25% risk increase per 1 mmol reduction) and chronic obstructive pulmonary disease (65% risk increase after 36 months). Conclusions: In our large, single-centre real-world analysis we identified the patients with the highest risk of death who could probably benefit the most from the most intensive therapy, and hence should be considered to be an 'extreme risk' population

Twist drill temperature determination using the pyrometric method

Jedną z pośrednich metod identyfikacji stanu ostrza w procesie skrawania jest pomiar temperatury. Temperatura skrawania to bardzo ważny czynnik wpływający zarówno na właściwości fizykalne materiału skrawanego jak i materiału narzędzia. Zjawiska cieplne występujące w strefie skrawania, a przede wszystkim temperatura ostrza, wpływają zdecydowanie na trwałość narzędzia, a w efekcie na koszt i wydajność obróbki. Artykuł przedstawia badania, które stanowią fragment prac związanych z opracowaniem modelu numerycznego do wyznaczania rozkładu temperatury ostrza narzędzia skrawającego na przykładzie procesu wiercenia. Celem badań było określenie pola temperatury składników procesu skrawania podczas wiercenia otworów wiertłem krętym, dla różnych parametrów skrawania, różnych średnic narzędzia oraz różnych właściwości powierzchni narzędzia. Badania przeprowadzono celem zweryfikowania przydatności metody pirometrycznej zaproponowanej w pracy [5].One of the indirect method of cutting edge condition identification during cutting process is the measurement of the cutting edge temperature. cutting temperature is the most important factor affecting for the physical and machining properties of the cutting material as well as for the tool material properties. Cutting zone phenomena, but first of all cutting temperature, is the most influencing factor for the tool life, and in the end for the cost and productivity of the machining process. The article present the part of researches for the numerical model of cutting zone temperature distribution determination for the drilling process. The main goal of the researches was to determine the temperature field distribution during the drilling with the various cutting parameters and tools diameter for the drilling with the twist drills with the different emissivity surface properties. The researches were made for the pyrometer method usability for the cutting temperature distribution determination during the drilling process

Global perspective of familial hypercholesterolaemia: a cross-sectional study from the EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC)

Background The European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration (FHSC) global registry provides a platform for the global surveillance of familial hypercholesterolaemia through harmonisation and pooling of multinational data. In this study, we aimed to characterise the adult population with heterozygous familial hypercholesterolaemia and described how it is detected and managed globally. Methods Using FHSC global registry data, we did a cross-sectional assessment of adults (aged 18 years or older) with a clinical or genetic diagnosis of probable or definite heterozygous familial hypercholesterolaemia at the time they were entered into the registries. Data were assessed overall and by WHO regions, sex, and index versus non-index cases. Findings Of the 61 612 individuals in the registry, 42 167 adults (21 999 [53·6%] women) from 56 countries were included in the study. Of these, 31 798 (75·4%) were diagnosed with the Dutch Lipid Clinic Network criteria, and 35 490 (84·2%) were from the WHO region of Europe. Median age of participants at entry in the registry was 46·2 years (IQR 34·3–58·0); median age at diagnosis of familial hypercholesterolaemia was 44·4 years (32·5–56·5), with 40·2% of participants younger than 40 years when diagnosed. Prevalence of cardiovascular risk factors increased progressively with age and varied by WHO region. Prevalence of coronary disease was 17·4% (2·1% for stroke and 5·2% for peripheral artery disease), increasing with concentrations of untreated LDL cholesterol, and was about two times lower in women than in men. Among patients receiving lipid-lowering medications, 16 803 (81·1%) were receiving statins and 3691 (21·2%) were on combination therapy, with greater use of more potent lipid-lowering medication in men than in women. Median LDL cholesterol was 5·43 mmol/L (IQR 4·32–6·72) among patients not taking lipid-lowering medications and 4·23 mmol/L (3·20–5·66) among those taking them. Among patients taking lipid-lowering medications, 2·7% had LDL cholesterol lower than 1·8 mmol/L; the use of combination therapy, particularly with three drugs and with proprotein convertase subtilisin–kexin type 9 inhibitors, was associated with a higher proportion and greater odds of having LDL cholesterol lower than 1·8 mmol/L. Compared with index cases, patients who were non-index cases were younger, with lower LDL cholesterol and lower prevalence of cardiovascular risk factors and cardiovascular diseases (all p<0·001). Interpretation Familial hypercholesterolaemia is diagnosed late. Guideline-recommended LDL cholesterol concentrations are infrequently achieved with single-drug therapy. Cardiovascular risk factors and presence of coronary disease were lower among non-index cases, who were diagnosed earlier. Earlier detection and greater use of combination therapies are required to reduce the global burden of familial hypercholesterolaemia. Funding Pfizer, Amgen, Merck Sharp & Dohme, Sanofi–Aventis, Daiichi Sankyo, and Regeneron