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.

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.

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.

Lipoprotein Apheresis for Lipoprotein(a)-Associated Cardiovascular Disease: Prospective 5 Years of Follow-Up and Apolipoprotein(a) Characterization.

OBJECTIVE: Lipoprotein(a)-hyperlipoproteinemia (Lp(a)-HLP) along with progressive cardiovascular disease has been approved as indication for regular lipoprotein apheresis (LA) in Germany since 2008. We aimed to study the long-term preventive effect of LA and to assess hypothetical clinical correlations of apolipoprotein(a) (apo(a)) by analyzing genotypes and phenotypes. APPROACH AND RESULTS: This prospective observational multicenter study included 170 patients with Lp(a)-HLP and progressive cardiovascular disease (48.9 years median age at diagnosis) despite other cardiovascular risk factors, including low-density lipoprotein cholesterol had maximally been treated (mean baseline low-density lipoprotein cholesterol: measured, 2.56 mmol/L [98.9 mg/dL] and corrected, 1.72 mmol/L [66.3 mg/dL]). Patients were prospectively investigated during a 5-year period about annual incidence rates of cardiovascular events. In addition, apo(a) isoforms and polymorphisms at the apo(a) gene (LPA) were characterized. One hundred fifty-four patients (90.6%) completed 5 years of follow-up. Mean Lp(a) concentration before commencing regular LA was 108.1 mg/dL. This was reduced by a single LA treatment by 68.1% on average. Significant decline of the mean annual cardiovascular event rate was observed from 0.58±0.53 2 years before regular LA to 0.11±0.15 thereafter (P<0.0001); 95.3% of patients expressed at least 1 small apo(a) isoform. Small apo(a) isoform (35.2%) carrying phenotypes were not tagged by single-nucleotide polymorphisms rs10455872 or rs3798220. CONCLUSIONS: Results of 5 years of prospective follow-up confirm that LA has a lasting effect on prevention of cardiovascular events in patients with Lp(a)-HLP. Patients clinically selected by progressive cardiovascular disease were characterized by a highly frequent expression of small apo(a) isoforms. Only Lp(a) concentration seemed to comprehensively reflect Lp(a)-associated cardiovascular risk, however.

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.

Lipoprotein apheresis in patients with maximally tolerated lipid-lowering therapy, lipoprotein(a)-hyperlipoproteinemia, and progressive cardiovascular disease: prospective observational multicenter study.

BACKGROUND: Lipoprotein(a) (Lp(a)) hyperlipoproteinemia is a major risk factor for cardiovascular disease, which is not affected by treatment of other cardiovascular risk factors. This study sought to assess the effect of chronic lipoprotein apheresis (LA) on the incidence of cardiovascular events in patients with progressive cardiovascular disease receiving maximally tolerated lipid-lowering treatment. METHODS AND RESULTS: In a prospective observational multicenter study, 170 patients were investigated who commenced LA because of Lp(a)-hyperlipoproteinemia and progressive cardiovascular disease. Patients were characterized regarding plasma lipid status, lipid-lowering drug treatment, and variants at the LPA gene locus. The incidence rates of cardiovascular events 2 years before (y-2 and y-1) and prospectively 2 years during LA treatment (y+1, y+2) were compared. The mean age of patients was 51 years at the first cardiovascular event and 57 years at the first LA. Before LA, mean low-density lipoprotein cholesterol and Lp(a) were 2.56±1.04 mmol·L(-1) (99.0±40.1 mg·dL(-1)) and Lp(a) 3.74±1.63 µmol·L(-1) (104.9±45.7 mg·dL(-1)), respectively. Mean annual rates for major adverse coronary events declined from 0.41 for 2 years before LA to 0.09 for 2 years during LA (P<0.0001). Event rates including all vascular beds declined from 0.61 to 0.16 (P<0.0001). Analysis of single years revealed increasing major adverse coronary event rates from 0.30 to 0.54 (P=0.001) for y-2 to y-1 before LA, decline to 0.14 from y-1 to y+1 (P<0.0001) and to 0.05 from y+1 to y+2 (P=0.014). CONCLUSIONS: In patients with Lp(a)-hyperlipoproteinemia, progressive cardiovascular disease, and maximally tolerated lipid-lowering medication, LA effectively lowered the incidence rate of cardiovascular events. CLINICAL TRIAL REGISTRATION URL: https://drks-neu.uniklinik-freiburg.de. Unique identifier: DRKS00003119.

Longitudinal cohort study on the effectiveness of lipid apheresis treatment to reduce high lipoprotein(a) levels and prevent major adverse coronary events.

BACKGROUND: We investigated in a longitudinal, multicenter, cohort study whether combined lipid apheresis and lipid-lowering medication can reduce extremely high levels of lipoprotein(a) (Lp[a]) and thus prevent major adverse coronary events (MACE) more efficaciously than lipid-lowering medication alone. METHODS: Eligible patients had coronary artery disease and Lp(a) levels > or =2.14 micromol/l (95th percentile). All patients received lipid-lowering medications alone until maximally tolerated doses were no longer effective, followed by combined lipid apheresis and lipid-lowering medication. The rates of the primary outcome, MACE, were recorded for both periods. RESULTS: A total of 120 patients were included. The mean duration of lipid-lowering therapy alone was 5.6+/-5.8 years, and that of apheresis was 5.0+/-3.6 years. Median Lp(a) concentration was reduced from 4.00 micromol/l to 1.07 micromol/l with apheresis treatment (P<0.0001); the corresponding mean annual MACE rate per patient was 1.056 versus 0.144 (P<0.0001). CONCLUSIONS: Lowering of Lp(a) levels by apheresis was efficacious and safe, and we recommend this therapy for patients in whom maximally tolerated doses of medication alone have failed to control coronary artery disease-associated events.