Actual situation of lipoprotein apheresis in patients with elevated lipoprotein(a) levels

Atherosclerosis Supplements 40 (2019) 1e7

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Actual situation of lipoprotein apheresis in patients with elevated lipoprotein(a) levels Ulrich Julius*, Sergey Tselmin, Ulrike Schatz, Sabine Fischer, Andreas L. Birkenfeld, Stefan R. Bornstein Lipidology and Center for Extracorporeal Treatment, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische €t Dresden, Germany, Fetscherstr. 74, 01307, Dresden, Germany Universita

a b s t r a c t Keywords: Lipoprotein apheresis Lipoprotein(a) LDL-Cholesterol Triglycerides Cardiovascular events

An elevation of lipoprotein(a) (Lp(a)) is an internationally recognized atherogenic risk factor, documented in epidemiological studies, in studies with Mendelian randomization and in genome-wide association studies (GWAS). At present, no drug is available to effectively reduce its concentration. In Germany, an elevation of Lp(a) associated with progressive cardiovascular diseases is officially recognized as an indication for a lipoprotein apheresis (LA). The number of patients who were treated with LA with this abnormality was steadily increasing in the years 2013e2016 e the official data are reported. In all new patients, who started to be treated at our LA center in 2017 (n ¼ 20) the increased Lp(a) was a main indication for extracorporeal therapy, though some of them also showed clearly elevated LDL cholesterol (LDL-C) concentrations despite being treated with a maximal tolerated lipid-lowering drug therapy. A diabetes mellitus was seen in 5 patients. The higher was the Lp(a) level before the first LA session, the higher was the cardiovascular risk. Lp(a) concentrations measured before LA sessions were usually about 20% lower than those before the start of the LA therapy. Acutely, Lp(a) levels were reduced by about 70%. Following LA sessions the Lp(a) levels increased and in the majority reach pre-session concentrations after one week. Thus a weekly interval is best for the patients, but a few may need two sessions per week to stop the progress of atherosclerosis. The interval mean values were about 39% lower than previous levels. Several papers had been published showing a higher efficiency of LA therapy on the incidence of cardiovascular events in patients with high Lp(a) values when comparing with hypercholesterolemic patients with normal Lp(a) concentrations. Russian specific anti-Lp(a) columns positively affected coronary atherosclerosis. PCSK9 inhibitors reduce Lp(a) concentrations in many patients and in this way have a positive impact on cardiovascular outcomes. In the future, an antisense oligonucleotide against apolipoprotein(a) may be an alternative therapeutic option, provided a clear-cut reduction of cardiovascular events will be demonstrated. © 2019 Published by Elsevier B.V.

1. Introduction In the last years, lipoprotein(a) (Lp(a)) emerged as an important atherogenic risk factor, though it had been described already in 1963 and was shown to play a role in the development of cardiovascular diseases in observational studies in the 1990ies [1,2]. Recently, the significance of Lp(a) was demonstrated in more epidemiological studies, in studies using a Mendelian randomization and in genome-wide association studies (GWAS) [3e6]. Both,

* Corresponding author. E-mail address: [email protected] (U. Julius). https://doi.org/10.1016/j.atherosclerosissup.2019.08.043 1567-5688/© 2019 Published by Elsevier B.V.

high Lp(a) concentrations and a low Kringle IV Type 2 number are independently associated with cardiovascular diseases like myocardial infarction, stroke, peripheral arterial occlusive disease, and aortic aneurysm. An aortic valve stenosis may also be seen [7]. Among individuals with high Lp(a), nearly 30% of myocardial infarction cases and nearly 50% of aortic stenosis cases could be attributed to high Lp(a) [8]. Neither nutrition nor physical activity exert an influence on Lp(a) levels. A hormone deficit in women in the post-menopausal age or renal diseases may increase Lp(a) concentrations. It is well known that patients affected by a familial hypercholesterolemia have often increased Lp(a) concentrations [9]. Lipid-lowering drugs like statins, fibrates, ezetimibe do not

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influence Lp(a). Nicotinic acid reduced Lp(a) levels by about 20%. In intervention studies PCSK9 inhibitors decreased Lp(a) concentrations by about 25e30% [10]. Also mipomersen and CETP inhibitors showed a reducing action. In drug studies published so far, an effect of a reduction of elevated Lp(a) concentrations on the incidence of cardiovascular events could not be demonstrated [11]. Due to this fact and serious adverse effects, nicotinic acid was withdrawn from the market in 2013 [12]. In the recently published ODYSSEY OUTCOMES and FOURIER trials, baseline Lp(a) appeared to be an independent risk factor for cardiovascular events (CVEs) [10]. The rather modest PCSK9 inhibitor-induced decrease of Lp(a) was associated with a reduction of CVEs in both studies, independently of the changes in LDLcholesterol (LDL-C). At present, an effective therapeutic tool in our hands to minimize the atherogenic risk associated with elevated Lp(a) levels represents the lipoprotein apheresis (LA). This indication is realized in several countries like Germany, USA, Great Britain, Austria, and Italy [13]. In Germany, the Joint Federal Committee (G-BA) accepted an elevation of Lp(a) as an indication for LA in 2008 [14], in the antecedent years some patients were treated following a court order.

Lp(a)  120 nmol/l (Table 2). Except in 2016, male patients were seen more often than females. The mean age of all groups was between 50 and 60 years. The number of patients of Group 1 went down from 8 (about one third) in 2014e2015 to zero in 2017. In this context it is noteworthy that in 2013 among all patients (n ¼ 89) who were treated with LA at our center 31 patients (34.8%)

Table 2 New patients at our LA center in 2014e2017 subdivided into different hyperlipidemic groups e number, age, gender, associated risk factors, lipid-lowering drugs. Group 1

Group 2

Group 3

10 6 m/4 f 51 34e77

7 5 m/2 f 60 36e77

13 5 m/8 f 58 38e75

7 2 m/5 f 59 44e75

16 13 m/3 f 57 41e75

4 3 m/1 f 60 52e69

10 26.9 21e39 8 3

7 29.4 24e42 7 2

13 28.73 23e34 10 2

7 27.4 25e29 5 1

16 27.7 23e35 15 4

4 26.2 17e32 3 1

10 9/0 6 1

7 6/1 4 0

13 7/0 8 1

7 2/3 5 0

16 16/0 10 0

4 3/1 3 0

2014e15 n 25 males/females mean age (years) range

8 5 m/3 f 61 31e73

n 21 males/females mean age (years) range

1 0 m/1 f 59

n 20 males/females mean age (years) range

0

2016

2017

1.1. LA in Germany In Germany, three indications for an LA are officially recognized [15]: 1. Homozygous familial hypercholesterolemia, 2. Severe hypercholesterolemia associated with cardiovascular diseases and an LDL-C value above the internationally recommended target, additional risk factors have to be taken into consideration, 3. Elevation of Lp(a) above 60 mg/dl (or 120 nmol/l) and (clinically or by imaging technique) documented progressive cardiovascular diseases, the LDL-C value has to be optimized by drug therapy when tolerated. Numbers of patients treated with LA in Germany are given in Table 1 according to the underlying diagnosis for the years 2013e2016 [16e19]. In each year, about 500 patients started the extracorporeal therapy. The percentage of patients with the indication “elevation of Lp(a)” increased from 53% of these new patients in 2013 to 73% in 2016. These numbers reflect the growing acceptance of the elevated Lp(a) as a risk factor among treating physicians and patients as well. 1.2. LA at our center e new patients in 2014e2017

2014e15 n 25 mean BMI (kg/m2) range Hypertension Diabetes

8 29.3 24e39 6 5 2016

n 21 mean BMI (kg/m2) range Hypertension Diabetes

1 32 1 0 2017

n 20 mean BMI (kg/m2) range Hypertension Diabetes

0

n 25 Statin/Intolerance Ezetimibe Fibrate

8 5/2 3 0

n 21 Statin/Intolerance Ezetimibe Fibrate

1 0/1 0 0

n 20 Statin/Intolerance Ezetimibe Fibrate

0

2014e15

We subdivided the new patients into 3 hyperlipidemic groups according to their LDL-C and Lp(a) concentrations before the first LA session: Group 1: LDL-C  2.6 mmol/l (100 mg/dl) and Lp(a) < 120 nmol/l, Group 2: LDL-C < 2.6 mmol/l (100 mg/dl) and Lp(a)  120 nmol/l, Group 3: LDL-C  2.6 mmol/l (100 mg/dl) and Table 1 Numbers of patients treated with LA in Germany in 2013e2016 (at the end of each year; published in the Quality reports of the National Association of Statutory Health Insurance Physicians (KBV) 2014 to 2017). Year hoFH Severe HCH Isolated Lp(a) Total

2013

2014

2015

2016

187 1221 753 (35%) 2161

120 1472 954 (37%) 2546

122 1597 1303 (43%) 3022

103 1700 1468 (45%) 3271

Abbreviations: hoFH e homozygous familial hypercholesterolemia; HCH e hypercholesterolemia.

2016

2017

Abbreviation: BMI e body mass index.

U. Julius et al. / Atherosclerosis Supplements 40 (2019) 1e7

still belonged to Group 1 with normal or not-detectable Lp(a). Obesity was present in several patients. The vast majority suffered from arterial hypertension. The percentage of patients with diabetes mellitus clearly decreased between 2014 and 2017. Statin intolerance was present only in a few patients. Ezetimibe was used quite frequently, fibrates only in two patients. It has to be stressed that no patient starting LA therapy received a PCSK9 inhibitor. Fig. 1 contains the number of cardiovascular events (myocardial infarction, stroke, occlusion of peripheral arteries, interventions like vascular operation or PTA or PTCA) per patient in dependence on the concentrations of Lp(a) and LDL-C measured before the first LA session in the patients (n ¼ 20) starting apheresis in 2017. In all new patients in 2017, Lp(a) levels were clearly above 120 nmol/l. The higher this concentration was the more events per patient were observed. Two patients suffered from events in two different vascular territories. In 5 patients, only one event took place (4 patients with coronary events). Usually, these patients had atherosclerosis at other vascular regions as well or developed their event at a rather young age or had a positive family history with respect to cardiovascular events in first-degree relatives. The majority underwent at least 2 events, mostly at the same vascular site. 3 patients reported 4 events, 1 six events, and 1 eight events. As shown in Table 2, among the new patients in 2017 only 4 had LDL-C levels higher than 2.6 mmol/l (100 mg/dl). Several patients had cardiovascular events in the past, though their actual LDL-C levels were in the optimal range at the first LA session. It can be suspected that the LDL-C levels were higher at the time when the CVE occurred.

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elevated Lp(a) concentrations with respect to the reduction of cardiovascular events by more than 80% was demonstrated in one retrospective study [20] and one prospective study [21,22]. Both studies involved several LA centers and various LA systems have been used. In general, LA systems reduce both Lp(a) and LDL-C levels, and it is difficult to differentiate which reduction is responsible for the cardiovascular effects. On the other hand, Russian specific PocardR Lp(a) columns, which do not have a significant influence on LDL-C, induced a beneficial effect on coronary atherosclerosis assessed by coronary angiography [23]. A single-blinded randomized controlled trial was conducted in 20 patients with refractory angina and raised Lp(a) > 50 mg/dl, with 3 months of blinded weekly LA or sham, followed by crossover after a 4 weeks interval between the extracorporeal procedures [24]. The true LA sessions increased myocardial perfusion, improvements with apheresis compared with sham also occurred in atherosclerotic burden as assessed by total carotid wall volume (assessed by MRT), exercise capacity by the 6 min walk test, 4 of 5 domains of the Seattle angina questionnaire and quality of life physical component summary by the short form 36 survey (SF-36). In several case studies the efficiency of LA was compared in patients with normal and with elevated Lp(a) levels (Table 3) [25e28]. It could be demonstrated that an LA therapy is much more effective with respect to the percent reduction of cardiovascular events in patients whose Lp(a) concentrations were elevated. 1.4. Lp(a) levels during LA treatment

1.3. Study evidence The excellent effectiveness of an LA therapy in patients with

Lp(a) is acutely reduced by LA sessions, usually by more than 60%. It goes up again in the following days. Thus a sawtooth picture can be observed. After approximately 7 days the Lp(a) concentration is up again. Thus it makes sense to perform LA sessions in weekly intervals. In a previous paper we had reported about our experience with LA in patients (n ¼ 59) with elevated Lp(a) concentrations till the end of 2013 [29]. Lp(a) levels were measured by immuno LEIA antihuman Lp(a) Latex Reagent. We described an increase of Lp(a) levels measured before LA sessions in the long run in half of the patients, in a quarter these values remained stable, and in another quarter these levels were decreased. Fig. 2 represents a recalculation of these data from the publication by Gross et al. [29] The interval mean (IM) values have been calculated according to Kroon et al. [30]. When comparing with the situation before the start of the LA therapy, both Lp(a) and LDL-C levels were lower when measured immediately before the LA sessions. With respect to the concentrations after the end of LA sessions, these reductions were still more expressed: (Lp(a) e112 mg/dl or e77%, LDL-C e2.6 mmol/l or e76%). The difference of the IM values amounted to e57 mg/dl or e39% for Lp(a) and to e1.3 mmol/l or e38%. Starting from 2014, in our lab an assay of the second generation was used for measuring Lp(a) levels: Immunoassay for

Table 3 Case studies comparing the efficiency of an LA therapy on cardiovascular events in patients with normal Lp(a) and with elevated Lp(a) levels e reduction (percent) when comparing events before LA treatment and during LA therapy.

Fig. 1. Cardiovascular events in new patients in 2017 e in dependence on Lp(a) (Fig. 1 A) and on LDL-C (Fig. 1 B) concentrations.

First author

Year

von Dryander [25] Emmrich [26] Heigl [27] Schatz [28]

2013 2015 2015 2017

Normal Lp(a) -

54% 33% 74% 53%

Elevated Lp(a) -

83% 85% 90% 75%

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Fig. 2. Recalculation of the data of Tables 2 and 3 of Gross et al. [29] e Lp(a) (mg/dl) e Fig. 2 A - and LDL-C (mmol/l) e Fig. 2 B - levels before start of LA therapy, pre-LA- and post-LAsessions and interval mean (IM) values. Comparisons were made with the levels observed before the start of the LA therapy and with pre-session levels.

lipoprotein(a) (WHO/IFCC International Reference Reagent) - SRM 2B using the device Roche/Hitachi Cobas c 701/702. The antibodies identifying the not repetitive Kringle IV domains enabled a more precise measurement of Lp(a) particles concentrations [31]. In a publication on the kinetics of Lp(a) following LA sessions we had proposed a simple new formula to calculate IM values for Lp(a) values obtained in nmol/l [32]. The most recently (August 2018) measured Lp(a) and LDL-C levels before and after an LA session in all 130 patients (mean age: 63 years e range 35e86; 82 males, 48 females; mean duration of LA: 5 years e range 0e26 years), who at present are treated with LA at our center, are summarized in Table 4. We use 6 different LA

systems [33]. The vast majority of the patients are treated with LA once per week (n 106), 3 patients twice per week, 16 biweekly, 4 monthly, and one patient comes to our center every 8 weeks. In 19 patients (14.6%) Lp(a) concentrations were either not detectable or < 120 nmol/l at their first LA session. All patients were on a lipid-lowering drug therapy (statins, ezetimibe; PCSK9 inhibitor in single cases) when tolerated. In 29 patients the pre-session Lp(a) values were below 120 nmol/l, though they initially had higher Lp(a) concentrations. In the mean, Lp(a) levels were reduced by the LA sessions by 130.22 nmol/l (74.11%). The IM values amounted to 118.22 nmol/l in the mean with a wide range of observed concentrations. The

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Table 4 Lp(a) (nmol/l; n ¼ 111) and LDL-C (mmol/l; n ¼ 130) levels measured before and after one LA session in August 2018 and interval mean (IM) values (for Lp(a) calculated according to Tselmin et al., 2017 [32]; for LDL-C according to Kroon et al. [30]).

m SD MIN MAX

m SD MIN MAX

Lp(a)pre

Lp(a)post

Lp(a)-absD

Lp(a)-relD (%)

Lp(a)-IM

Lp(a)IM-absD

Lp(a)IM-relD (%)

175.78 75.70 58.00 420.00

45.57 23.55 10.00 135.00

130.22 57.69 43.00 313.00

74.11 7.15 49.72 91.69

118.22 57.69 31.00 301.00

57.57 23.55 22.00 147.00

34.06 7.90 12.14 56.91

LDLCpre

LDLCpost

LDLC-absD

LDLC-relD (%)

LDLC-IM

LDLIM-absD

LDLIM-relD (%)

2.22 0.83 0.52 4.96

0.67 0.32 0.12 1.94

1.55 0.63 0.39 4.03

69.79 8.98 34.21 88.35

1.80 0.67 0.41 4.03

0.42 0.17 0.11 1.09

18.84 2.42 9.24 23.85

Abbreviations: m e mean value SD e standard deviation. pre e pre LA sessions post e post LA sessions -absD e absolute difference -relD (%) e relative difference. IM-absD e interval mean absolute difference IM-relD (%) e interval mean relative difference (%).

absolute difference between pre-session levels and IM values was 57.57 nmol/l, corresponding to a reduction by 34.06%. Reduction rates for both LDL-C and Lp(a) observed in August 2018 were quite similar to those seen up to 2013. The efficacy of all available LA methods with respect to lowering of Lp(a) was comparable (Onefactorial ANOVA; data not shown). The numbers given in Table 4 represent real-world data. Some patients started LA only recently, usually the efficiency with respect to lowering of Lp(a) and LDL-C will be optimized in the course of a continuing extracorporeal therapy, e. g. by increasing the treated volume. In some patients the rebound after LA sessions is faster, presession values are reached already after 3 days. In these patients two sessions per week are needed, especially when new CVE appeared on the background of an LA therapy. 1.5. PCSK9 inhibitors and Lp(a) in patients on LA therapy In PCSK9 inhibitor studies a reduction of 25e30% of Lp(a) levels has been seen. But it cannot be neglected that the majority of these patients had Lp(a) concentrations in the normal range. Waterfall plots show a differing response of Lp(a) to PCSK9 inhibitors [34]. In the ODYSSEY ESCAPE study where Alirocumab was added to an LA therapy no effect of this drug on Lp(a) levels has been demonstrated in those patients with high Lp(a) concentrations [35]. In our own experience in LA patients with high Lp(a) concentrations, we can confirm that Lp(a) is differently reduced by the PCSK9 inhibitor injections. In any case, an elevation of Lp(a) is no indication to administer these drugs. 1.6. Antisense oligonucleotide against apo(a) A promising new antisense oligonucleotide against apolipoprotein(a) had been studied in Phase 1 and 2 studies [36,37]. It decreased Lp(a) concentrations very effectively, more than 90%. Phase 3 studies will soon start. In contrast to LA, the Lp(a) levels remain very low all the time and the medication has to be applied in big intervals. 2. Discussion This paper reports the experience with LA in one of the biggest LA centers in Germany, working at a University Hospital. At our center, an elevation of Lp(a) played an increasing role as an indication to treat patients with LA. In 2013, 34.8% of our patients (n ¼ 89) did not show a high Lp(a), in 2018 only 14.6% (total number of patients 130). An important criterion of the quality of an LA therapy is the

acute reduction rate of both Lp(a) and LDL-C concentrations by LA sessions. This paper shows excellent results in this respect, though in single patients e especially in those who started LA only recently e a further improvement is still needed. In 2010, a European Atherosclerosis Society Consensus Panel [3] wrote the following statement: “Finally, in young or middle-aged patients with evidence of progressive coronary disease and markedly elevated plasma Lp(a), serious consideration should be given to instituting LDL apheresis which removes Lp(a) efficaciously; however, this form of treatment is prohibitively expensive and impractical for most patients and most clinical centers.” The situation in Germany convincingly shows that LA is an efficacious therapeutic approach to save lives in high-risk patients, and that LA is feasible in practical medicine. The studies documenting the results have been published in high-ranking journals [20e22]. Here the situation with respect to the incidence of CVE has been compared before the start of an LA therapy and during the extracorporeal treatment. From an ethical point of view, a randomized controlled study was not accepted. Though the Multiselect study tries to circumvent this problem [38]. Another criticism is that the better medical care for the apheresis patients (they see a doctor regularly, get advice with respect to lifestyle, are reminded to take their drugs, get psychological support during the LA sessions from the apheresis staff) may even be more important than the extracorporeal therapy itself. This opinion is contradicted by the finding that an LA therapy in patients with elevated Lp(a) levels is more efficient with respect to outcome data than this therapy in patients with hypercholesterolemia (and normal Lp(a) concentrations) e all these patients are treated in the same way. In epidemiological studies, it has been shown that CVE may develop at lower Lp(a) concentrations than the accepted level for the indication of an LA (60 mg/dl and 120 nmol/l, respectively) [13,39]. Undoubtedly, this limit was fixed arbitrarily e also in order to avoid an extremely high number of patients requiring the LA therapy. Probably, the IM values point to the remaining atherogenic risk in LA patients. In both observation periods described in this paper (up to 2013 and thereafter), we were able to reach acceptable Lp(a) IM values. Though in some patients with extremely high initial Lp(a) concentrations this was not possible. In single patients, we switched to a regime of 2 LA sessions per week. But in general, the reduction of the incidence of CVE during LA therapy is impressive. In a recently published paper using a Mendelian Randomization Analysis it was concluded that a lower Lp(a) concentration is associated with a lower coronary risk [40]. The authors wrote that the results of their study suggest that pharmacologically lowering Lp(a) concentration by approximately 100 mg/dl should reduce the

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risk of coronary heart disease (death or nonfatal myocardial infarction) by approximately 22%e25% in a 3- to 5-year randomized trial, similar to the association that has been observed for a 1 mmol/l (38.67 mg/dl) reduction in LDL-C level during treatment with a statin. But it cannot be overlooked that the majority of patients of the studies included into this paper exhibit much lower Lp(a) concentrations than those defined as a criterion for LA therapy. Moreover, an LA therapy resulted in a much greater reduction of CVE in patients with high Lp(a) levels. Thus the proposed calculated effects did not take into account the rich experience with extracorporeal therapy at all. Of course the LDL-C level is a therapeutic target in all patients with high Lp(a). Our data about the new patients entering our center in 2017 clearly show that this approach was successful, though none of them was already on a PCSK9 inhibitor therapy. In epidemiological studies it was demonstrated that LDL-C and Lp(a) are independent atherogenic risk factors [41]. Russian specific PocardR Lp(a) columns proved that an isolated reduction of Lp(a) was effective with respect to progression of atherosclerotic coronary lesions. They may be especially helpful in patients whose true (after correction of the LDL-C value by subtracting the LDL-C contained in Lp(a) particles from the measured LDL-C concentration) is very low. The official recommendation is that measuring Lp(a) once in a person will be sufficient. Of course, in LA patients this parameter is assessed regularly. When patients missed an LA session, the Lp(a) level will go up till the next session still more than usually. In outpatients (not on LA) treated at our lipidological center some variation of Lp(a) concentrations was seen, a fact that has recently been described by others [42]. 3. Conclusions Nowadays LA remains an effective tool to reduce the extremely high atherogenic risk in patients with elevated Lp(a) levels. The extracorporeal therapy is usually very well tolerated [43]. Of course, it is invasive, laborious (needs the presence of a physician and a technician (nurse)), cost-expensive, is offered by a limited number of out- or in-patient facilities in countries except Germany. But it has to be taken into consideration that by avoiding new CVE money will be saved. A more widespread use of this tool is desirable. The effect of LA therapy on CVE can be seen already in the first year after initiation of the extracorporeal therapy, while lipidlowering drugs, including statins and PCSK9i, need at least several months to show a benefit [44]. Despite a continuing LA therapy, a few patients develop new CVE. The reasons for these complications still remain obscure in patients who are compliant with respect to lifestyle and to drug intake. The future will show whether a combination of an LA therapy and an injection therapy with PCSK9 inhibitors will improve this situation. An antisense oligonucleotide against apolipoprotein(a) will probably offer a therapeutic alternative to LA. However studies will be needed to show its long-term safety and effect on cardiovascular outcome [45]. In single patients with extremely high Lp(a) concentrations, suffering from CVEs despite being treated with LA, this antisense oligonucleotide could be used as an orphan drug. In a recently published paper, S. Tsimikas recommended to compare LA, which affects multiple lipid and viscosity and other parameters and lowers levels of PCSK9, to Lp(a)-lowering therapies that only affect Lp(a) levels [46]. Conflicts of interest UJ: honoraria from Aegerion, Akcea, Amgen, Chiesi, Sanofi,

Kaneka, Diamed, Fresenius Medical Care, MSD. ST: received honoraria for lectures and consulting by Amgen, Fresenius Medical Care, Kaneka, MSD, and Sanofi-Aventis. US: No conflicts of interest relevant to this publication. SF: honoraria from Sanofi, Amgen, MSD, Berlin-Chemie, Abbott, Boehringer Ingelheim. ALB: honoraria from Sanofi and Amgen. SRB: none to declare. Acknowledgements This article is part of a supplement entitled ‘Therapeutic Apheresis e Current advances for the treatment of metabolic, cardiovascular and autoimmune diseases. Based on the contributions to the 2nd Congress of the European Group e International Society for Apheresis, March 22-24, 2018, Vienna, Austria’, published with support of the European Group e International Society for Apheresis e E-ISFA office. E-ISFA gratefully acknowledges support of this supplement by B. Braun, DIAMED Medizintechnik, Fresenius Medical Care, and Kaneka. References [1] Julius U. History of lipidology and lipoprotein apheresis. Atherosclerosis Suppl 2017;30:1e8. https://doi.org/10.1016/j.atherosclerosissup.2017.05.034. [2] Kostner KM, Kostner GM. Lipoprotein (a): a historical appraisal. J Lipid Res 2017;58:1e14. https://doi.org/10.1194/jlr.R071571. [3] Nordestgaard BG, Chapman MJ, Ray K, Boren J, Andreotti F, Watts GF, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 2010;31:2844e53. https://doi.org/10.1093/eurheartj/ehq386. [4] Tsimikas SA. Test in context: lipoprotein(a): diagnosis, prognosis, controversies, and emerging therapies. J Am Coll Cardiol 2017;69:692e711. https:// doi.org/10.1016/j.jacc.2016.11.042. [5] Tselmin S, Muller G, Gelgaft E, Fischer S, Julius U. An elevated lipoprotein(a) plasma level as a cardiovascular risk factor. Atherosclerosis Suppl 2015;18: 257e62. https://doi.org/10.1016/j.atherosclerosissup.2015.02.038. [6] Gencer B, Kronenberg F, Stroes ES. Mach, F. Lipoprotein(a): the revenant. Eur Heart J 2017;38:1553e60. https://doi.org/10.1093/eurheartj/ehx033. [7] Langsted A, Varbo A, Kamstrup PR, Nordestgaard BG. Elevated lipoprotein(a) does not cause low-grade inflammation, despite causal association with aortic valve stenosis and myocardial infarction: a study of 100,578 individuals from the general population. J Clin Endocrinol Metab 2015:jc20151096. [8] Afshar M, Thanassoulis G. Lipoprotein(a): new insights from modern genomics. Curr Opin Lipidol 2017;28:170e6. https://doi.org/10.1097/ MOL.0000000000000392. [9] Li S, Wu NQ, Zhu CG, Zhang Y, Guo YL, Gao Y, et al. Significance of lipoprotein(a) levels in familial hypercholesterolemia and coronary artery disease. Atherosclerosis 2017;260:67e74. https://doi.org/10.1016/ j.atherosclerosis.2017.03.021. [10] Julius U, Tselmin S, Schatz U, Fischer S, Bornstein SR. Lipoprotein(a) and proprotein convertase subtilisin/kexin type 9 inhibitors. Clin Res Cardiol Suppl 2019;14:45e50. https://doi.org/10.1007/s11789-019-00099-z. [11] Julius U. Niacin as antidyslipidemic drug. Can J Physiol Pharmacol 2015;93: 1043e54. https://doi.org/10.1139/cjpp-2014-0478. [12] Julius U, Fischer S. Nicotinic acid as a lipid-modifying drug–a review. S15675688(12)00047-5 [pii] Atherosclerosis Suppl 2013;14:7e13. https://doi.org/ 10.1016/j.atherosclerosissup.2012.10.036. [13] Hanssen R, Gouni-Berthold I. Lipoprotein(a) management: pharmacological and apheretic treatment. Curr Med Chem 2017;24:957e68. https://doi.org/ 10.2174/0929867324666170112110928. [14] Bundesministerium für Gesundheit. Bekanntmachung eines Beschlusses des € Gemeinsamen Bundesausschusses über eine Anderung der Richtlinie Meth€rztliche Versorgung: apherese bei isolierter Lp(a)-Erho €hung. oden vertragsa BAnz 2008;138:3321. [15] Julius U. Current role of lipoprotein apheresis in the treatment of high-risk patients. J Cardiovasc Dev Dis 2018;5. 10.3390/jcdd5020027. €rztliche. Qualita €tsbericht - Ausgabe 2014 [16] Bundesvereinigung Kassena Berichtsjahr 2013. Special edition. www.kbv.de; 2014. €rztliche. Qualita €tsbericht - Ausgabe 2015 [17] Bundesvereinigung Kassena Berichtsjahr 2014. Special edition. www.kbv.de; 2015. €rztliche. Qualita €tsbericht - Ausgabe 2016 [18] Bundesvereinigung Kassena Berichtsjahr 2015. Special edition. www.kbv.de; 2016. €rztliche. Qualita €tsbericht - Ausgabe 2017 [19] Bundesvereinigung Kassena Berichtsjahr 2016. Special edition. www.kbv.de; 2017. [20] Jaeger BR, Richter Y, Nagel D, Heigl F, Vogt A, Roeseler E, et al. Longitudinal cohort study on the effectiveness of lipid apheresis treatment to reduce high lipoprotein(a) levels and prevent major adverse coronary events. Nat Clin Pract Cardiovasc Med 2009;6:229e39. ncpcardio1456 [pii];10.1038/

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