Current situation of lipoprotein apheresis in Saxony

Atherosclerosis Supplements 14 (2013) 51e55 www.elsevier.com/locate/atherosclerosis

Current situation of lipoprotein apheresis in Saxony U. Julius*, K. Taseva, S. Fischer, J. Passauer, S.R. Bornstein Department of Internal Medicine III, University Hospital Carl Gustav Carus Dresden, Fetscherstr. 74, 01307 Dresden, Germany

Abstract This paper summarizes the situation pertinent to treatment via lipoprotein apheresis in the federal state of Saxony, Germany in 2010. In total, 119 predominately male patients were treated in 10 centers; the majority of the patients was older than the mean age of the general population. Several risk factors were present, particularly a familial predisposition and hypertension. All patients had experienced cardiovascular events and the majority was taking statins. Patient data from the University Hospital Carl Gustav Carus in Dresden concurred with data derived from patients treated at nephrological practices. In the mean, patients attended the centers for about 6 years, the majority weekly. LDL cholesterol concentrations prior to apheresis were clearly higher than target levels; apheresis sessions decreased LDL cholesterol by 69%. Lipoprotein(a) levels could be measured in 75 patients and were effectively reduced by lipoprotein apheresis. In Saxony, 29 patients per 1 million inhabitants received lipoprotein apheresis, which is higher than the proportion of patients treated in Germany as a whole. The need for this extracorporeal treatment seems to be much greater than its current utilization. Among the patients only one homozygous patient with familial hypercholesterolemia was observed. Physicians should be actively informed about this therapeutic possibility to reduce the cardiovascular risk efficiently. The introduction of new drugs may alter the position of lipoprotein apheresis within the therapeutic spectrum. Ó 2012 Elsevier Ireland Ltd. All rights reserved. Keywords: Cardiovascular diseases; High atherogenic risk; LDL cholesterol; Lipoprotein(a); Lipoprotein apheresis; Saxony (Germany)

1. Introduction Lipoprotein apheresis (LA) is an effective tool for reducing the incidence of cardiovascular events in patients with a high atherogenic risk due to severe hyperlipoproteinemia. Worldwide, Germany, where the reimbursement by the health insurance companies has been officially defined by the Federal Joint Committee (Gemeinsamer Bundesausschuss) [1], has the highest number per capita of patients being treated with this extracorporeal therapy [2]. Three indications have been accepted: 1. Homozygous familial hypercholesterolemia (FH); 2. Severe hypercholesterolemia, if a maximum

* Corresponding author. Tel.: þ49 351 458 2306; fax: þ49 351 458 5306. E-mail address: [email protected] (U. Julius). 1567-5688/$ - see front matter Ó 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.atherosclerosissup.2012.10.003

documented dietetic and drug therapy for more than 1 year failed to lower LDL cholesterol (LDL-C) sufficiently; and, 3. Elevation of Lipoprotein(a) (Lp(a)) above 600 mg/l together with progressive cardiovascular disease documented clinically or by imaging techniques. Germany is a republic consisting of 16 federal states, including Saxony, the capital of which is Dresden. The first lipoprotein apheresis session was conducted in Dresden in November 1990, after the reunification [3]. The Saxonian Association of Statutory Health Insurance Physicians authorizes nephrologists to perform lipoprotein apheresis in their own medical practices. At the end of 2010, nine nephrological centers and the Apheresis Center at the University Hospital Carl Gustav Carus in Dresden (UHD) treated patients with this extracorporeal approach. Four more centers were authorized but did not have patients yet. This paper describes the situation in Saxony in the end of 2010 and compares it with that of Germany as a whole,

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especially in a Bavarian region (Allga¨u). Additionally, it compares the efficiency of the LA treatment at the UHD with that at other centers.

Table 2 Number of patients in apheresis centers (1 ¼ University Hospital Dresden).

2. Material and methods Six lipoprotein apheresis methods were used, for details about these methods see the literature [4e10] (Table 1). In 2010, 119 patients were treated with lipoprotein apheresis in Saxony (Table 2), more than half of them at the UHD Apheresis Center. The other centers were located in Dresden, Riesa, Leipzig, Weisswasser, Lo¨bau, Zittau, Hoyerswerda, Plauen, and Annaberg-Buchholz. Lipid concentrations were measured before and immediately after apheresis using standard biochemical methods. This paper focuses on LDL-C and Lp(a). The data underlying this evaluation were collected by K. Taseva who visited all centers and had personal contact with each patient. All patients agreed that their data could be used in an anonymous form. Statistical comparisons (t-test) were made using the SPSS 18.0 program. 3. Results The patients were predominantly male, which is in contrast to the general population in Saxony: at UHD: 62.5% were males and 37.5% females; at other centers: 58.2% were males, and 41.8% females. The general population is comprised of 49% males and 51% females. The mean age at the beginning of the apheresis treatment was clearly higher than the mean age in the general population: UHD: males 56.9 years (maximum: 75 years, minimum: 38 years), females 55.2 years (maximum: 78 years, minimum: 32 years); other centers: males 50.3 years (maximum: 74 years, minimum: 18 years), females 54 years (maximum: 73 years, minimum: 17 years); general population: males 44.2 years, females 48 years.

C Filtration - Lipidfiltration (LF; DIAMED Medizintechnik GmbH, Cologne, Germany) - MONET (Fresenius Medical Care GmbH, Bad Homburg, Germany) C Adsorption - DALI (Fresenius Medical Care GmbH, Bad Homburg, Germany) - Liposorber D (Kaneka Pharma Europe N.V., Wiesbaden, Germany) - TheraSorb LDL (antibodies; Miltenyi Biotec GmbH, Bergisch Gladbach, Germany) Abbreviations: HELP: heparin-induced extracorporeal lipoprotein precipitation, MONET: membrane filtration optimised novel extracorporeal treatment, DALI: direct adsorption of lipoproteins.

Number

1 2 3 4 5 6 7 8 9 10

64 3 19 2 6 2 1 8 6 8

Fig. 1 summarizes the prevalence of further risk factors observed in the apheresis patients. Obesity was defined by a Body Mass Index higher than 30 kg/m2. A genetic defect means that in these patients a mutation either in the LDL receptor gene or in the apolipoprotein B gene (3500) had been identified. The familial predisposition describes the occurrence of cardiovascular diseases in relatives or the presence of hyperlipidemia in relatives. Type 1 diabetes mellitus and Type 2 diabetes mellitus reflect a known diagnosis. An impaired glucose tolerance (IGT) was seen during an oral glucose tolerance test. Hypertension was defined as patients taking antihypertensive drugs. A familial predisposition and hypertension were found in the vast majority of the patients. No major differences with respect to risk factors were seen between the patients treated at the UHD and at the other centers, respectively. In fact, in all patients cardiovascular events had occurred before the start of the apheresis therapy (Fig. 2). In the vast majority of patients a coronary angiography had been performed; several patients had undergone coronary stenting. Only at the UHD patients were treated after heart transplantation (to prevent a deterioration of a proven

8989

8886

100

Table 1 Classification of lipoprotein apheresis methods.

80

%

C Precipitation - HELP (B. Braun Melsungen AG, Melsungen, Germany)

Center

60 40

44 34

40 3135 31

20

2 0

0

UHD

13 7

Other centers

Fig. 1. Risk factors in the apheresis patients at the UHD and at the other centers.

Number of patients

U. Julius et al. / Atherosclerosis Supplements 14 (2013) 51e55

60 50 40 30 20 10 0

53

Table 4 Lipoprotein apheresis methods (%) used in the centers.

5050 31 30 25 2327 26

38 34 26 23

17 14 2

UHD

6

1113

24 18 8

5

5

0

Other centers

Fig. 2. Cardiovascular events in the apheresis patients before the start of the apheresis therapy at the UHD and at the other centers. CHD: coronary heart disease (documented by angiography), MI: myocardial infarction, New AP: angina pectoris, CABG coronary arteries bypass grafting, Reocclusion/restenosis (in the majority of cases after stent implementation), ACI stenosis: arteria carotis interna, ACE stenosis: arteria carotis externa, PAOD: peripheral arterial occlusive disease.

transplant vasculopathy) [11]. With respect to other cardiac events, patients of the UHD and the other centers were comparable. Simvastatin and/or ezetimibe were widely used (Table 3). 9 patients at the UHD and 9 patients at the other centers did not tolerate any statin or ezetimibe. Whereas in the UHD Apheresis Center five apheresis methods were used, the DALI and HELP methods clearly dominate in the other centers (Table 4). The intervals between apheresis sessions are given in Table 5. At the UHD Apheresis Center 7 patients undergoing treatment for many years are subjected to apheresis once per month or less. In former years, in single cases more than one session was performed per week in special situations (high LDL-C level immediately after a cardiovascular event). This also was done at the Leipzig apheresis center in 2010. In the mean, patients at the UHD and the other apheresis centers have been treated with LA for approximately 6 Table 3 Lipid-modifying drugs in the apheresis patients (numbers of patients and percentages).

Simvastatin Pravastatin Atorvastatin Rosuvastatin Fluvastatin Ezetimibe Bile acid sequestrants Nicotinic acid Fibrates Omega3FA Omega3FA: omega 3 fatty acids.

UHD

Other centers

31 6 8 4 8 34 5 13 2 8

26 1 6 3 4 30 8 11 1 17

(48.4%) (9.4%) (12.5%) (6.3%) (12.5%) (53.1%) (7.8%) (20.3%) (3.1%) (12.5%)

(47.3%) (1.8%) (10.9%) (5.5%) (7.3%) (54.5%) (14.5%) (20.0%) (1.8%) (30.9%)

DALI MONET HELP LF TheraSorb LDL Liposorber D

UHD

Other centers

26.6 0 22 20 22 9.4

72.7 1.8 16.4 5.5 0 3.6

years (UHD Apheresis Center: maximum 20 years, minimum 2 months; other centers: maximum 18.5 years, minimum 2 months). LDL-C concentrations before apheresis ranged between 3 and 4 mmol/l; they did not differ among the patients of the UHD and the other centers (Fig. 3). Maximum LDL-C levels, however, did differ: UHD 7.81 mmol/l, other centers 12.87 mmol/l. The high LDL-C is seen in a female patient with homozygous FH (Cincinatti mutation of the LDL receptor gene). Mean reduction rates of LDL cholesterol achieved by apheresis sessions were 69% in both the UHD (maximum: 88%, minimum: 39%) and the other centers (maximum: 95%, minimum 26%). Kroon et al. [12,13] suggested calculating the interval means of LDL-C by using the following formula: Cmean ¼ Cmin þ KðCmax  Cmin Þ where Cmax is the LDL-C concentration before apheresis sessions, Cmin after the sessions. K was proposed to be 0.73. The interval mean of LDL-C in the patients at the UHD was 2.63  1.01 mmol/l, at the other centers 2.91  1.42 mmol/l (the difference is not statistically different). Lp(a) was not detectable in 25 patients of the UHD and in 19 patients from the other centers. Mean values before and after apheresis in the other patients are given in Fig. 4. For the patients at the UHD the maximum of Lp(a) was 2218 mg/l, the minimum 70 mg/l; at the other centers the maximum amounted to 3050 mg/l, the minimum to 124 mg/l. In both subgroups the mean Lp(a) concentrations after apheresis were less than 350 mg/l. In the patients at the UHD the mean reduction rates of Lp(a) were 69  2.75% (maximum 95%, minimum 45%),

Table 5 Intervals between apheresis sessions (number of patients and percentages).

Weekly Biweekly Once per month Once in 8 weeks Twice per week

UHD

Other centers

44 13 6 1 0

41 10 0 0 4

(68.8%) (20.3%) (9.4%) (1.6%) (0.0%)

(74.5%) (18.2%) (0.0%) (0.0%) (7.3%)

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4 3.5

mmol/l

3 2.5 2 1.5 1 0.5 0

1_LDLC pre

1_LDLC post

2_LDLC pre

2_LDLC post

Fig. 3. LDL-C concentrations before (pre) and after (post) apheresis (Group1: UHD, Group 2: other centers).

at the other centers 63  1.83% (maximum 86%, minimum 26%). The difference in the mean reduction rates between the two subgroups was statistically significant ( p ¼ 0.013). 4. Discussion This is the first paper reporting the apheresis situation in a federal state of Germany. Throughout Germany about 1500 patients are treated with lipoprotein apheresis (A. Ramlow 2011, 3. Wiener Apherese-Seminar, Vienna 2011). In 2010, the total population of Germany was 81,702,329. Taking that into account, lipoprotein apheresis was used in 18 per 1 Mio inhabitants. This sums up to about 70,000 treatments per year. In Germany approximately 2.8 Mio people suffer from CHD or myocardial infarction and need to reach target LDL-C levels below 2.6 mmol/l, or, in selected cases, below 1.8 mmol/l [2]. Of these patients, at least 1% (equaling 28,000 patients, or 340:1,000,000) will miss these targets with drug therapy alone, and thus qualify

for apheresis [2]. Saxony had a population of 4,100,000 people. In 2010, 23,941 people died from cardiovascular diseases (Saxonian Office of Statistics 2011). According to data published by Bruckenberger [14] in Saxony the mortality rate after myocardial infarction was 21.3% higher than the average age-adjusted mortality rate throughout Germany. In Saxony 119 patients were on lipoprotein apheresis in the end of 2010 (29 per 1 Mio inhabitants; about 5200 treatments per year). When extrapolating the data given above, 1394 Saxonian patients would need LA. In other words, only about 10% of those with an indication were actually treated with apheresis. Heigl 2009 [2] wrote that in the Allga¨u region 170:1,000,000 patients actually received apheresis treatment (estimated to equal 50% of those with a clear-cut indication). Thus, the situation in Saxony is better than that in the whole of Germany but is worse than in the Allga¨u region. When examining the reduction rates of LDL-C and Lp(a) and the interval means of LDL-C, the efficiency of LA therapy in Saxony can be described as good, although the mean value of Lp(a) after apheresis sessions did not reach the normal range (below 250 mg/l). The comparison between the Apheresis Center at the UHD and the other centers did not show major differences in the effectiveness. This conclusion is restricted by the fact that in four centers less than five patients are on treatment so far. According to the estimated prevalence of homozygous FH, 4 homozygous FH patients should live in Saxony. To our knowledge only one is being treated with lipoprotein apheresis. Usually patients are referred to apheresis centers by family doctors, cardiologists or specialists in vascular medicine. From the data above it is evident that the possibility of this extracorporeal treatment modality is not known to many physicians and should be made more public. 5. Conclusions

1200 1000

mg/l

800 600 400 200 0

1_Lpa pre

1_Lpa post

2_Lpa pre

2_Lpa post

Fig. 4. Lp(a) concentrations before (pre) and after (post) apheresis (Group1: UHD, Group 2: other centers).

Saxony is a federal state of Germany with a rather high morbidity and mortality due to cardiovascular diseases. In patients with a very high atherogenic risk due to severe hyperlipoproteinemia, lipoprotein apheresis is a proven treatment option to improve their vascular risk. The frequency of apheresis treatment in Saxony can be described as rather good (especially when comparing with other countries) but far from optimal (when looking at the high cardiovascular morbidity). In our opinion an apheresis center should offer more than one lipoprotein apheresis method [15], although this is only realistic when a center treats more than five patients annually. In the future, the relevance of apheresis will need to be reconsidered when new therapeutic options such as apolipoprotein B-100 antisense (Mipomersen) find their way into clinical practice [13,16].

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Conflits of interest In the last 3 years, the corresponding author was reimbursed travel expenses by Diamed, Fresenius, and B. Braun. He was paid honoraria for lectures by MSD and Fresenius as well as for lipidologic evaluations by Fresenius. The other authors state that they do not have anything to declare.

[6]

[7]

[8]

Acknowledgements The authors wish to thank the patients, the physicians and the nurses at the apheresis centers for their support of this evaluation.

[9]

[10]

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