Effective exosomes reduction in hypercholesterinemic patients suffering from cardiovascular diseases by lipoprotein apheresis: Exosomes apheresis.

INTRODUCTION: Extracellular vesicles (EVs) have been identified as playing a role in atherosclerosis. METHODS: A group of 37 hypercholesterolemic patients with atherosclerotic cardiovascular diseases (ASCVD) and 9 patients requiring hemodialysis (HD) were selected for the study. RESULTS: EVs were comparably reduced by various LA methods (Thermo: 87.66% ± 3.64, DALI: 87.96% ± 4.81, H.E.L.P.: 83.38% ± 11.98; represented as SEM). However, LDL-C (66%; 55%; 75%) and Lp(a) (72%; 67%; 79%) were less effectively reduced by DALI. There was no significant difference in the reduction of EVs when comparing different techniques, such as hemoperfusion (DALI; n = 13), a precipitation (H.E.L.P.; n = 5), and a double filtration procedure (Thermofiltration; n = 19). Additionally, no effect of hemodialysis on EVs reduction was found. CONCLUSIONS: The study suggests that EVs can be effectively removed by various LA procedures, and this effect appears to be independent of the specific LA procedure used, as compared to hemodialysis.

[State of the art: lipoprotein apheresis]. / State of the Art: Lipoproteinapherese.

Lipoprotein apheresis (LA) is usually a last resort in cardiovascular high-risk patients in the context of secondary prevention after lifestyle measures and maximal pharmacotherapy have failed to prevent the occurrence of new atherosclerotic cardiovascular events (ASCVDE) or to achieve the internationally accepted target values for LDL cholesterol (LDL-C). Patients with homozygous familial hypercholesterolemia (hoFH), in whom myocardial infarctions can occur even in children < 10 years of age without adequate therapy, often owe their survival to LA (used here in primary prevention). Severe hypercholesterolemia (HCH) can often be well controlled with modern potent lipid-lowering agents, including PCSK9 approaches, so that the need for LA has decreased here over the years. In contrast, the number of patients in whom elevation of lipoprotein(a) (Lp(a)) is relevant to atherogenesis is increasing in applications to the apheresis committees of the associations of panel physicians (KV). For this indication, LA is currently the only therapeutic procedure approved by the Federal Joint Committee (G-BA). LA significantly reduces the new occurrence of ASCVDE (comparison with the situation before the start of LA), especially in Lp(a) patients. There are convincing observational studies and a German LA Registry with now 10-year data, but there is no randomized controlled trial. This had been requested by the G-BA in 2008, and a corresponding concept was designed but not accepted by the ethics committee. In addition to the highly effective reduction of atherogenic lipoproteins, many discussed pleiotropic effects of LA itself, the medical rounds and motivating discussions also with the nursing staff, which take place within the weekly LA, certainly contribute to the success of the therapy (steady adjustment of all cardiovascular risk factors, lifestyle measures including smoking cessation, adherence of medication intake). This review article summarizes and discusses the study situation, clinical practical experience as well as the future of LA against the background of the currently rapid development of new pharmacotherapies.

Beyond cholesterol-pleiotropic effects of lipoprotein apheresis.

Cardiovascular disease is a leading cause of mortality worldwide, which is caused mainly by atherosclerosis, a chronic inflammatory disease of blood vessels. Therefore, atherosclerosis represents a complex disorder, which induces damage or imbalance on different levels: for example, genes, cytokines, lipoproteins, cells, vessels, and organs. Lipoprotein apheresis (LA) is a well-established extracorporeal treatment of severe hyperlipoproteinemia. In addition, LA may have simultaneously crucial effects on many other atherogenic factors during the treatments, for example, as vascular inflammation, rheology, mobilization of adult stem cells and gene expressions in blood or endothelial cells, which will be discussed in this short review. In addition, stable microRNAs besides tissues also appear in extracellular compartments, for example, vessels, involved in atherosclerotic processes, were found to be reduced by LA treatments. In summary, LA represents a complex therapeutic procedure, that provides an ideal tool for the treatment of complex disorders such as atherosclerosis.

The German Lipoprotein Apheresis Registry-Summary of the ninth annual report.

During 2012-2020, 89 German apheresis centers collected retrospective and prospective observational data of 2028 patients undergoing regular lipoprotein apheresis (LA) for the German Lipoprotein Apheresis Registry (GLAR). More than 47 500 LA sessions are documented in GLAR. In 2020, all patients treated with LA showed a high immediate median reduction rate of LDL-C (68.2%, n = 1055) and Lp(a) (72.4%, n = 994). Patient data were analyzed for the incidence rate of major coronary events (MACE) 1 and 2 years before the beginning of LA treatment (y-2 and y-1) and prospectively up to 7 years on LA (y + 1 to y + 7). During the first 2 years of LA (y + 1 and y + 2), a MACE reduction of 78% was observed. Current analysis of GLAR data shows very low incidence rates of cardiovascular events in patients with high LDL-C and/or high Lp(a) levels, progressive ASCVD, and maximally tolerated lipid lowering medication regular by LA results.

Novel Insights into the Management of Patients with Very High Cardiovascular Risk Eligible for PCSK9 Inhibitor Treatment: Baseline Findings from the PERI-DYS Study.

AIM: The PERI-DYS study aims to characterize two groups of patients with dyslipidaemia at very high CV risk: PCSK9i receivers and patients qualifying for but not receiving PCSK9i. METHODS: This is an observational study by office-based and clinic-based physicians, mainly cardiologists and other internists in Germany, with data extracted from patient charts. CLINICALTRIALS: gov identifier NCT03110432. RESULTS: A total of 1659 patients were enrolled across 70 sites. The majority of patients (91.0%) were reported as having mixed dyslipidaemia or non-familial or heterozygous familial hypercholesterolemia. At enrolment, 794 (47.9%) of patients were PCSK9i receivers (of these 65.9% ongoing, and 34.1% newly treated within 30 days before their baseline visit). Among PCSK9i receivers, the majority had evolocumab 140 mg (n = 632, 38.1% of total). PCSK9i receivers compared to non-receivers were about 2 years younger and had a lower proportion of males. In terms of comorbidities, they had (statistically significantly) more often CAD, and less often PAD, diabetes mellitus, arterial hypertension and chronic renal disease. The calculated untreated median LDL-C was 187 mg/dl (IQR 127; 270) in ongoing PCSK9i receivers, 212 mg/dl (IQR 132; 277) in newly treated PCSK9i receivers, and 179 mg/dl (IQR 129; 257) in non-receivers. Physician-reported statin intolerance was much more common in the two PCSK9i receiver groups as compared to non-receivers (67.3% versus 15.3%). Consequently, patients in the PCSK9i groups received fewer concomitant statins. Mean total cholesterol (143 vs. 172 mg/dl) and LDL-C (69 vs. 99 mg/dl) were considerably lower in ongoing PCSK9i receivers compared to non-receivers. CONCLUSIONS: PCSK9i receivers are characterized by higher baseline LDL-C and a higher portion of statin intolerance compared to those qualified for but not-receiving PCSK9i treatment. On-treatment, LDL-C was lower in PCSK9i receivers. Ongoing follow-up will determine the prognostic importance of these findings.

Lipoprotein apheresis in Germany - Still more commonly indicated than implemented. How can patients in need access therapy?

BACKGROUND: Although lipid-lowering drugs, especially statins, and recently also PCSK9 inhibitors can reduce LDL cholesterol (LDL-C) and decrease the risk for cardiovascular disease (CVD) including coronary artery disease (CAD) events most efficiently, only 5-10% of high-risk cardiovascular patients reach the target values recommended by international guidelines. In patients who cannot be treated adequately by drugs it is possible to reduce increased LDL-C and/or lipoprotein(a) (Lp(a)) values by the use of lipoprotein apheresis (LA) with the potential to decrease severe CVD events in the range of 70%->80%. Even in Germany, a country with well-established reimbursement guidelines for LA, knowledge about this life-saving therapy is unsatisfactory in medical disciplines treating patients with CVD. Starting in 1996 our aim was to offer LA treatment following current guidelines for all patients in the entire region of our clinic as standard of care. METHODS: Based on the experience of our large apheresis competence center overlooking now nearly 80,000 LA treatments in the last two decades, we depict the necessary structure for identification of patients, defining indication, referral, implementation and standardisation of therapy as well as for reimbursement. LA is unfamiliar for most patients and even for many practitioners and consultants. Therefore nephrologists performing more than 90% of LA in Germany have to form a network for referral and ongoing medical education, comprising all regional care-givers, general practitioners as well as the respective specialists and insurances or other cost bearing parties for offering a scientifically approved therapeutic regimen and comprehensive care. The German Lipid Association (Lipid-Liga) has implemented the certification of a lipidological competence center as an appropriate way to realize such a network structure. RESULTS: Working as a lipidological and apheresis competence center in a region of 400,000 to 500,000 inhabitants, today we treat 160 patients in the chronic LA program. In spite of the availability of PCSK9 inhibitors since 2015, LA has remained as an indispensable therapeutic option for targeted lipid lowering treatment. An analysis of nearly 37,000 LA treatments in our own center documented a >80% reduction of cardiovascular events in patients treated by regular LA when comparing with the situation before the start of the LA therapy. We have implemented the concept of an apheresis competence center characterised by ongoing medical education with a focus on lipidological and cardiovascular aspects, interdisciplinary networking and referral. CONCLUSIONS: Incidence and prevalence of LA patients in our region demonstrate that based on our ongoing patient-centered approach the access of patients in need to LA is substantially above the German average, thus contributing to an extraordinary reduction of cardiovascular events in the population we in particular feel responsible for.

Real-world study: Escalating targeted lipid-lowering treatment with PCSK9-inhibitors and lipoprotein apheresis.

INTRODUCTION: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition with monoclonal antibodies has complemented the armamentarium of lipid-lowering therapy (LLT) before the final step of commencing chronic lipoprotein apheresis (LA). Data are scarce on patients who, after escalation of LLT with PCSK9 antibodies, have commenced chronic LA or PCSK9 antibody treatment during ongoing long-term LA. PATIENTS AND METHODS: In this study, a cohort of 110 patients with established atherosclerotic cardiovascular disease (ASCVD) due to hypercholesterolemia or concomitant lipoprotein(a)-hyperlipoproteinemia, who received PCSK9 antibodies for the first time during routine care, were consecutively identified. RESULTS: Mean LDL-C concentration prior to initiation of LA or PCSK9 antibody treatment was 5.3 ± 2.6 mmol/L (205 ± 102 mg/dL). Due to established ASCVD, the risk-adjusted LDL-C target value was <1.8 mmol/L (<70 mg/dL) in all patients. Use of PCSK9 antibodies increased the proportion of patients attaining the LDL-C target concentration by 41.8% overall. Treatment emergent adverse events (TEAE) associated with PCSK9 antibody medication were reported in 35 patients (31.8%). Discontinuation of PCSK9 antibody therapy due to TEAEs occurred in 25 patients (22.7%). CONCLUSION: Finally, 55.5% of patients received a combination of PCSK9 antibody therapy and LA at individually optimized treatment frequencies resulting in an increase of target attainment in 54.1% of patients. About 18.1% of chronic LA patients terminated LA treatment in this real-world study. The termination of long-term LA therapy, which has hitherto prevented the progression of ASCVD, requires careful individual risk assessment and cannot be recommended by the general criteria of LDL-C reduction.

Significance of Monoclonal PCSK9-Antibodies - New Approaches to the Therapy of Hypercholesterolemia.

Increased concentrations of low-density-lipoprotein (LDL)-cholesterol (LDL-C) and lipoprotein a (Lp(a)) are scientifically accepted, independent risk factors for the development of atherosclerosis. The complications of atherosclerosis occur early and more frequently. They are strongly linked with lifestyle factors and an increase of LDL-C concentrations in industrialized countries. A new therapeutic approach seems to be the modulation of the proprotein convertase subtilisin/kexin type 9 (PCSK9), which reduces the number of LDL-receptors at the cell membrane of the liver cells and thus increases the concentration of LDL-C in the blood. Results of current studies show, that in particular, a combination of PCSK9-AB and statins, independent of the dosage of the statins, is suitable to increase a reduction of LDL-C and Lp(a). This article gives an overview of the pathophysiology, the current study and research situation as well as the possible different approaches to the therapeutic influence of PCSK9 in the future.

First data from the German Lipoprotein Apheresis Registry (GLAR).

OBJECTIVE: In recent years the Federal Joint Committee (G-BA), a paramount decision-making body of the German health care system challenged the approval of diagnostic and therapeutic procedures for regular reimbursement, including lipoprotein apheresis therapy. Years before an interdisciplinary German apheresis working group, established by members of both German Societies of Nephrology (Verband Deutsche Nierenzentren (VDN), Deutsche Gesellschaft für Nephrologie (DGfN)), initiated a revision of the indication of lipoprotein apheresis therapy according to current guidelines and recommendations for the treatment of lipid disorders. This working group was convinced, that data derived from a registry would support lipoprotein apheresis as a therapy for severe hyperlipidemic patients suffering from progressive cardiovascular diseases. METHODS AND RESULTS: In 2009 the working group established the indication for lipoprotein apheresis with respect to current cardiovascular guidelines and scientific knowledge for the registry, which are in line with the reimbursement guidelines. In 2011 financing by sponsors was secured and an internet-based registry was created. A pilot project with 5 apheresis centers finished in 2012 - since then the registry is available to all German apheresis centers. CONCLUSIONS: There has been consensus between the medical societies and health care carriers regarding the need for a German Lipoprotein Apheresis Registry (GLAR). The launch of this registry complies with requirements of the Federal Joint Committee (G-BA). Complementing the Pro(a)LiFe-Study, first data from GLAR support the safety of the different apheresis treatment procedures. In addition these first data suggest, with respect to the results of Pro(a)LiFe-Study, effectiveness in preventing cardiovascular progression as well. Here, further data are needed to statistically substantiate these early findings.

Impact of the German Lipoprotein Apheresis Registry (DLAR) on therapeutic options to reduce increased Lp(a) levels.

BACKGROUND: The German Lipoprotein Apheresis Registry (DLAR) has been initiated by members of the Nephrology Foundation (WiNe), the German association of kidney centres (DN), the German society of nephrology (DGfN) and additional medical associations taking part in the apheresis working group. Its goal is the introduction of a substantial database, suitable to provide statistical evidence for the assessment of extracorporeal procedures. Data have been added to the DLAR since October 2011. In this article, preliminary results are first reported. METHODS AND RESULTS: Data are stored on a secured Internet platform. The recorded information comprises mean values and rates of change in lipid levels (cholesterol, triglyceride, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, lipoprotein(a) (Lp(a)) before and after apheresis therapy, blood/plasma volume, frequency and type of adverse effects, medication, vascular events, diagnoses and comorbidity. It is collected by participating apheresis centres from all over Germany. Up until October 2014, a total of 7946 lipoprotein apheresis (LA) treatments of 991 patients (787 with documented LDL-C and 688 with documented Lp(a) levels) via 96 medical accounts were documented and analysed. The current share of Lp(a) patients is 50.6 % (Lp(a) ≥ 60 mg/dl; n = 348/688). For both LDL-C and Lp(a), lowering rates exceeding 60 % have been observed. Likely in conjunction with these reduction rates, the preliminary analysis shows a 90 % decline in major adverse coronary events (MACE) as well as a decrease in major adverse non-coronary events (MANCE) by 69 %. As before, good tolerability and low rates of adverse effects (< 3 %) of LA therapy were found. CONCLUSIONS: The available numbers suggest in parts very good response by the participating centres to the DLAR. Unfortunately, there are also centres that have not documented any patients so far or LA treatments at all. The benchmark values for reduction rates in lipoprotein concentration required by the directives of the German Federal Joint Committee (G-BA) have all been met. The decrease in MACE and MANCE rates currently observed is very promising. However, the comparably short runtime of the registry does not allow for high confidence in the current results. Certainly, reliable data will be extractable in the coming years. Given the high interest expressed by European neighbours, the extension of the registry to the European level should be a future goal for the DLAR as well.