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.

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.

Alirocumab in patients with heterozygous familial hypercholesterolaemia undergoing lipoprotein apheresis: the ODYSSEY ESCAPE trial.

AIM: To evaluate the effect of alirocumab on frequency of standard apheresis treatments [weekly or every 2 weeks (Q2W)] in heterozygous familial hypercholesterolaemia (HeFH). METHODS AND RESULTS: ODYSSEY ESCAPE (NCT02326220) was a double-blind study in 62 HeFH patients undergoing regular weekly or Q2W lipoprotein apheresis. Patients were randomly assigned (2:1, respectively) to receive alirocumab 150 mg (n = 41) or placebo (n = 21) Q2W subcutaneously for 18 weeks. From day 1 to week 6, apheresis rate was fixed according to the patient's established schedule; from weeks 7 to 18, apheresis rate was adjusted based on the patient's low-density lipoprotein cholesterol (LDL-C) response in a blinded fashion. Apheresis was not performed when the LDL-C value was ≥30% lower than the baseline (pre-apheresis) value. The primary efficacy endpoint was the rate of apheresis treatments over 12 weeks (weeks 7-18), standardized to number of planned treatments. In the alirocumab group the least square (LS) mean ± SE (95% confidence interval [CI]) per cent change in pre-apheresis LDL-C from baseline at week 6 was -53.7 ± 2.3 (-58.2 to - 49.2) compared with 1.6 ± 3.1 (-4.7 to 7.9) in the placebo group. The primary efficacy endpoint showed statistically significant benefit in favour of alirocumab (Hodges-Lehmann median estimate of treatment difference: 0.75; 95% CI 0.67-0.83; P < 0.0001). Therefore, alirocumab-treated patients had a 0.75 (75%) additional reduction in the standardized rate of apheresis treatments vs. placebo-treated patients. During this period, 63.4% of patients on alirocumab avoided all and 92.7% avoided at least half of the apheresis treatments. Adverse event rates were similar (75.6% of patients on alirocumab vs. 76.2% on placebo). CONCLUSIONS: Lipoprotein apheresis was discontinued in 63.4% of patients on alirocumab who were previously undergoing regular apheresis, and the rate was at least halved in 92.7% of patients. Alirocumab was generally safe and well tolerated.

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.

Long-term effects of 3-month telemetric blood pressure intervention in patients with inadequately treated arterial hypertension.

BACKGROUND AND AIM: We have shown that better blood pressure (BP) control can be achieved by using 3-month telemetric BP measurement (TBPM) in comparison with a standard-care control group (C-G). The present analysis should clarify if this will also lead to a better middle- and long-term BP control. SUBJECTS AND METHODS: Fifty-seven patients finished the main study. After the 3 months no TBPM was performed. For 40 patients, 18 from the TBPM group (TBPM-G) and 22 from the C-G, we obtained ambulant BP measurements (ABPMs) with a mean follow-up of 20 months. Seventeen patients were lost to follow-up. BP target values were defined as ABPM ≤130/80 or ≤125/75 mm Hg with diabetes or renal failure. RESULTS: At the end of the follow-up, the systolic BP was 121.2±11.2 mm Hg in TBPM-G and 130.7±10.4 mm Hg in C-G, and the diastolic BP was 72.8±10.9 versus 77.0±7.1 mm Hg, respectively. Fifty-six percent in TBPM-G versus 40% in C-G (p=0.024) had a controlled BP as defined by ABPM criteria. CONCLUSIONS: TBPM helps achieve BP target values in patients with previously inadequately treated arterial hypertension, and the benefit is sustained. Beyond its immediate application, in comparison with standard treatment, TBPM allows for a better BP adjustment in the long term as well.

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.

Evolocumab-Based LDL-C Management in High and Very High Cardiovascular Risk Patients in German Clinical Practice: The HEYMANS Study.

INTRODUCTION: Low-density lipoprotein cholesterol (LDL-C) is among the most important modifiable risk factors for cardiovascular disease. In very high-risk patients, the European Society of Cardiology/European Atherosclerosis Society guidelines recommend attaining LDL-C < 55 mg/dL. In the German cohort of the observational HEYMANS study, we aimed to describe the clinical characteristics and LDL-C control among patients initiating evolocumab. METHODS: Data was collected between 09/2016 and 05/2021 for ≤ 6 months before (retrospectively) and ≤ 30 months after evolocumab initiation (prospectively). Patient characteristics, lipid-lowering therapy (LLT), lipid values, evolocumab use, and safety were collected. RESULTS: Of 380 enrolled patients, 93% received evolocumab in secondary prevention and 69% had a history of statin intolerance. At study baseline, 49% did not receive any statins and LDL-C was very high (145 mg/dL). Use of evolocumab decreased LDL-C by a median of 53% within 3 months and remained stable thereafter, despite mainly unchanged background LLT. Overall, 59% attained an LDL-C level < 55 mg/dL (69% with, 49% without LLT). Persistence to evolocumab was 90.6% in months 1-12 and 93.5% in months 13-30. Adverse drug reactions were reported in 8% of patients. CONCLUSION: Data from the German HEYMANS cohort corroborate previous reports on evolocumab effectiveness and safety in clinical practice. Evolocumab initiation was associated with a rapid and sustained LDL-C reduction. Persistence with evolocumab was high. Our finding that patients receiving an evolocumab/LLT combination are more likely to attain the LDL-C goal than those receiving evolocumab alone corroborates previous data showing the importance of using highly intensive therapy. Graphical abstract available for this article. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02770131 (registration date 27 April 2016).

Body weight telemetry is useful to reduce interdialytic weight gain in patients with end-stage renal failure on hemodialysis.

Lacking compliance with liquid intake restrictions is one of the major problems in patients on hemodialysis and causes an increased mortality. In 120 patients on hemodialysis with an average interdialytic weight gain (IWG) exceeding 1.5 kg on at least 2 days during the 4 weeks preceding the intervention, the effect of telemetric body weight measurement (TBWM) on IWG, ultrafiltration rate, and blood pressure was evaluated over a period of 3 months. Patients of the telemetric group (TG) were supplied with automatic scales, which transferred the weight via telemetry on a daily basis. In the case of IWG of more than 0.75 kg/24 h, a telephonic contact was made as required, and in the case of an IWG of more than 1.5 kg, telephonic contacting was obligatory along with the advice of a liquid intake restriction to 0.5 L/day until the next dialysis. The patients of the control group (CG) received standard treatment without telemetric monitoring. We examined specific data of the second interdialytic interval (IDI2) and the average within 1 week. The average difference of IWG between TG and CG was not significant before the start of the study but 0.2 kg (p=0.027) (IDI2)/0.27kg (p=0.001) (WP) at the end of the study, respectively. The average difference in the ultrafiltration rate within 1 week was 19.0 mL/h (p=0.282) (IDI2)/8.2 mL/h (p=0.409) before the start of the study but 28.4 mL/h (p=0.122) (IDI2)/30.9 mL/h (p=0.004) at the end of the study, respectively. Thus, TBWM is a feasible method for optimizing the IWG and reducing the ultrafiltration rate.

[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.

Pharmacokinetics and antihypertensive effects of candesartan cilexetil in patients undergoing haemodialysis: an open-label, single-centre study.

BACKGROUND AND OBJECTIVE: In patients with endstage renal failure (ERF), activation of the renin-angiotensin-aldosterone system plays an important role in the onset and maintenance of arterial hypertension. This study aimed to elucidate the antihypertensive effect, pharmacokinetics and safety of candesartan cilexetil in patients with ERF undergoing haemodialysis. METHODS: In 14 anuric hypertensive patients undergoing haemodialysis (mean+/- SD 24-hour systolic [SBP]/diastolic [DBP] blood pressure [BP] 142.9 +/- 11.1/75.0 +/- 10.1 mmHg), 24-hour BP measurements on the second interdialysis day per week were performed at baseline and at weeks 4, 12 and 24. All patients started antihypertensive treatment with candesartan cilexetil 4 mg once daily immediately before the start of haemodialysis. Subsequently, the dose was titrated upward to 8 mg once daily until the patient's mean ambulatory BP measurement (ABPM) values were <130/80 mmHg. Plasma candesartan pharmacokinetics were investigated on days 7 and 14 after starting candesartan cilexetil treatment and after each titration step. RESULTS: After 6 months all patients demonstrated well controlled BP (ABPM mean +/- SD SBP 129.6 +/- 21.7/DBP 69.4 +/- 10.4 mmHg) and a significantly reduced pulse pressure (from a mean +/- SD 67.9 +/- 13.7 mmHg at baseline to a mean +/- SD 60.2 +/- 14.7 mmHg at 6 months), without any adverse events. Candesartan plasma concentrations increased over 3 hours followed by a continuous decline. Plasma concentrations remained stable after 7 and 14 days, independent of dosing. However, administration of candesartan cilexetil 8 mg (five patients) resulted in plasma concentrations about 1.4 times higher than those for candesartan cilexetil 4 mg. CONCLUSION: In this study with small number of patients with ERF undergoing haemodialysis, candesartan cilexetil was effective in lowering BP and pulse pressure without accumulation or associated adverse effects such as elevated potassium or symptomatic hypotension.

Lipoprotein(a) - Marker for cardiovascular risk and target for lipoprotein apheresis.

Lipoprotein(a) (Lp(a)) consists of an LDL particle whose apolipoprotein B (apoB) is covalently bound to apolipoprotein(a) (apo[a]). An increased Lp(a) concentration is a causal, independent risk factor for atherosclerotic cardiovascular disease (ASCVD) and a predictor of incident or recurrent cardiovascular events. Although Lp(a) was first described as early as 1963, only the more recent results of epidemiological, molecular, and genetic studies have led to this unequivocal conclusion. More than 20% of Western populations have elevated Lp(a) values. Lp(a) concentrations should be always part of the lipid profile when ASCVD risk is assessed. However, presence of other risk factors, laboratory findings, medical history and family history must be considered to conclude on its clinical relevance in an individual patient. Early or progressive ASCVD or a familial predisposition are key findings which can be associated with elevated Lp(a). The cholesterol portion contained in Lp(a) is also included in the various methods of LDL-C measurement. To assess proximity to the cardiovascular risk related target value for LDL-C, appropriate correction should be applied when high Lp(a) values are obtained to estimate the LDL-C that can actually be treated by lipid lowering drugs. Initial study data show that antisense oligonucleotides, which selectively decrease apolipoprotein(a), are promising as future treatment options. Currently, lipoprotein apheresis, which has a reimbursement guideline in Germany, is the therapy of choice for patients with Lp(a)-associated progressive ASCVD, with the aim of sustained prevention of further cardiovascular events.

NMR-based lipoprotein analysis for patients with severe hypercholesterolemia undergoing lipoprotein apheresis or PCSK9-inhibitor therapy (NAPALI-Study).

Taking into account the discordance between low-density lipoprotein cholesterol (LDL-C) and LDL particle (LDL-P) number, cardiovascular risk more closely correlates with LDL-P in patients. The aim of our study was to evaluate the number of lipid particles in patients with severe hypercholesterolemia treated with different lipid-lowering regimens. Four groups of patients differing with respect to lipid-lowering therapy were recruited from hypercholesterolemic outpatients and lipoprotein apheresis (LA) facilities, and were treated with statins alone (group A), with statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (PCSK9i) (group B), with statins and LA (group C), or with statins, PCSK9i, and LA (group D). Cholesterol, triglycerides, LDL-C, high-density lipoprotein cholesterol (HDL-C), LDL-P number and size, HDL-P number and size were determined using nuclear magnetic resonance spectroscopy. The lowest LDL-P number was achieved at the end of LA sessions in combination with statins or in combination with statins and a monoclonal PCSK9i (median; 25th and 75th percentile) (group C: 244 nmoL/L: 237, 244, P < 0.05; group D: 244 nmoL/L: 99, 307, P < 0.05). Comparing LDL-P number at the start of LA (group C: 978 nmoL/L: 728, 1404; group D: 954 nmoL/L: 677, 1521) to the other patient groups (groups A and B), the lowest LDL-P number was measured in patients treated with PCSK9i and a statin (group B): LDL-P (762 nmoL/L: 604, 1043, P < 0.05), large LDL-P (472 nmoL/L: 296, 574, P < 0.05), and small LDL-P (342 nmoL/L: 152, 494, P < 0.05). Very low-density lipoprotein and HDL particle sizes remained approximately the same in all groups. LA in combination with statins or in combination with statins and PCSK9i most reduced LDL-P numbers in hypercholesterolemic patients.

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.

Efficacy of lipid reduction with DALI and MONET.

BACKGROUND: Lipidapheresis techniques are increasingly used to treat drug-resistant hyperlipidemia but few efficacy studies under routine application are available. In this multicenter observational study we investigated direct adsorption of lipoproteins (DALI) and lipoprotein filtration (MONET) for the short and the long-term effects on lipid-lowering effects. METHODS: Data of 122 apheresis patients from 11 centers (DALI: n = 78, MONET: n = 44) were prospectively collected for a period of 2 years. Routine lipid measurements were evaluated (2154 DALI and 1297 MONET sessions). It was investigated whether the relative reduction of LDL-C during apheresis session achieves at least 60%. Also relative reduction of total cholesterol, HDL, triglyceride, and Lp(a) were analyzed. RESULTS: The relative reduction of LDL-C was at least 60%: DALI: 70.62%, 95% CI = [69.34; 71.90] and MONET: 64.12%, 95% CI = [60.79; 67.46]. Also triglycerides were reduced with both systems: DALI 38.63%, 95% CI = [33.95; 43.30] vs. MONET 57.68%, 95% CI = [51.91; 63.45]. Relative reductions of total cholesterol were in the range of 50% (DALI 95% CI = [46.49; 49.65] MONET 95% CI = [48.93; 55.26]) and of Lp(a) in the range of 65% (DALI 95% CI = [61.92; 65.83] MONET 95% CI = [63.71; 70.30]. HDL reduction was: DALI 15.01%, 95% CI = [13.22; 16.79] and MONET 22.59%, 95% CI = [19.33; 25.84]. For both devices treated patient plasma/blood volume and in case of DALI the use of the larger adsorber configurations (DALI 1000 and DALI 1250) were independent positive predictors of the relative reduction of LDL-C and of Lp(a). CONCLUSIONS: Both systems effectively improved lipid profile and reduced atherogenic lipids. The results point to the importance of the individualized application of these valuable therapies to achieve clinical targets.

Lipidological competence centres and networks: Future perspectives to improve healthcare of patients with disorders of lipid metabolism.

BACKGROUND: Numerous healthcare studies have shown that more than 90% of all patients with dyslipidaemia are not treated adequately. OBJECTIVES: The "Deutsche Gesellschaft zur Bekämpfung von Fettstoffwechselstörungen und ihren Folgeerkrankungen (DGFF)" [German Society of Lipidology], a non-profit professional membership organization, has already made a series of efforts to improve the care of patients suffering from dyslipidaemia. A recent outcome is the nationwide implementation and certification of Lipidological Competence Centres and Networks (LCCNs). METHODS AND RESULTS: By involving numerous external medical cooperation partners and combining the detailed work of different in-house medical specialists, the Medical Care Centre Kempten-Allgäu was able to improve both the diagnosis and treatment of patients exhibiting disorders of lipid metabolism (DLM). This local lipidological network is so successful, that it may serve as a nationwide standard model for outpatient lipidological care. Detailed organizational structures for improved lipidological care which are suitable to provide a template for future guidelines for the certification of LCCNs have been developed by the Medical Care Centre Kempten-Allgäu. Stringent requirements of implementation with respect to medical staff, content and structure, staff training, patient education and public relations as well as to documentation, quality assurance and quality improvement must be fulfilled both by the lipidological competence centre (LCC) and the cooperation partners within the lipidological network (LN). Finally, members of the health care system (e.g. health policy and health insurances) should be involved in this attempt and convinced of financial support. CONCLUSION: The implementation and certification of national LCCNs supported by DGFF could contribute to a comprehensive improvement in the care of patients with dyslipidaemia, resulting in prevention of cardiovascular diseases and reduction of cardiovascular sequelae.

Safety aspects of lipidapheresis using DALI and MONET - Multicenter observational study.

BACKGROUND: Lipidapheresis was introduced for intractable hyperlipidemia as a more selective therapy than plasma exchange aiming to enhance efficacy and limit side-effects. Although this therapy is regarded safe, multicenter data from routine application are limited. We investigated direct adsorption of lipoproteins (DALI) and lipofiltration (MONET) regarding the short and the long-term safety aspects. METHODS: This multicenter observational study prospectively evaluated 2154 DALI and 1297 MONET sessions of 122 patients during a period of 2 years. Safety parameters included clinical side-effects (adverse device effects, ADEs), technical complications, blood pressure and pulse rate. Also routinely performed laboratory parameters were documented. Analysis of laboratory parameters was not corrected for blood dilution. RESULTS: Overall 0.4% DALI and 0.5% MONET treatments were affected by ADE. Technical complications occurred in 2.1% and in 0.8% DALI and MONET sessions, respectively. The most frequent ADE was hypotension, and the majority of technical problems were related to vascular access. Both types of treatments led to a drop of thrombocytes in the range of 7-8%. Hematocrit and erythrocytes decreased only during the DALI treatments by about 6%. Leucocytes decreased during the DALI therapy (∼15%), whereas they increased during the MONET application (∼11%). MONET treatment was associated with a higher reduction of proteins (fibrinogen: 58% vs. 23%, albumin: 12% vs. 7%, CRP: 33% vs. 19% for MONET and DALI, respectively). Apart from severe thrombocytopenia in two DALI patients, changes of other parameters were typically transient. CONCLUSIONS: Under routine use the frequency of side-effects was low. Still, monitoring of blood count and proteins in chronic apheresis patients is recommended.

Toward an international consensus-Integrating lipoprotein apheresis and new lipid-lowering drugs.

BACKGROUND: Despite advances in pharmacotherapy of lipid disorders, many dyslipidemic patients do not attain sufficient lipid lowering to mitigate risk of atherosclerotic cardiovascular disease. Several classes of novel lipid-lowering agents are being evaluated to reduce atherosclerotic cardiovascular disease risk. Lipoprotein apheresis (LA) is effective in acutely lowering the plasma concentrations of atherogenic lipoproteins including low-density lipoprotein cholesterol and lipoprotein(a), and novel lipid-lowering drugs may dampen the lipid rebound effect of LA, with the possibility that LA frequency may be decreased, in some cases even be discontinued. SOURCES OF MATERIAL: This document builds on current American Society for Apheresis guidelines and, for the first time, makes recommendations from summarized data of the emerging lipid-lowering drug classes (inhibitors of proprotein convertase subtilisin/kexin type 9 or microsomal triglyceride transfer protein, high-density lipoprotein mimetic), including the available evidence on combination therapy with LA with respect to the management of patients with dyslipidemia. ABSTRACT OF FINDINGS: Recommendations for different indications are given based on the latest evidence. However, except for lomitapide in homozygous familial hypercholesterolemia and alirocumab/evolocumab in heterozygous familial hypercholesterolemia subjects, limited data are available on the effectiveness and safety of combination therapy. More studies on combining LA with novel lipid-lowering drugs are needed. CONCLUSION: Novel lipid-lowering agents have potential to improve the performance of LA, but more evidence is needed. The Multidisciplinary International Group for Hemapheresis TherapY and Metabolic DIsturbances Contrast scientific society aims to establish an international registry of clinical experience on LA combination therapy to expand the evidence on this treatment in individuals at high cardiovascular disease risk.