German Haemapheresis Centre

Comparison of different Lp(a) Elimination Techniques:

A retrospective Evaluation



  H. Borberg

German Haemapheresis Centre

ESFH Congress Düsseldorf 2008

ABSTRACT

Lipoprotein (a), abbreviated Lp (a), is accepted as a potential selective or additional risk factor for premature atherosclerosis. Though it may be considered to be closely related to low density lipoprotein, so far attempts to keep it under control with diet or cholesterol lowering medications have failed. Thus, extracorporeal elimination is the only effective treatment approach for patients with premature atherosclerosis. As different techniques for differential elimination such as precipitation, adsorption and filtration exist, it appeared of interest for us to retrospectively evaluate adsorption and filtration procedures in their capacity to lower Lp (a). 4 patients with selectively elevated Lp(a) and 8 patients with familial hypercholesterolaemia and additional elevated Lp(a) could be evaluated. All patients had Lp (a) values of 80 - 120 mg/dl without treatment in common. Different plasma or whole blood volumes were processed to obtain 20 - 40 mg/dl Lp(a) as post-treatment target values. In patients with a selective elevation Lp (a) apheresis, as developed from Prokovski, was the most potent elimination procedure, decreasing the Lp (a) by at least 81 % of the initial value after processing 6 litres of plas-ma followed from LDL-(immune) apheresis with 71 %. Plasma differential filtration using the Kuraray LA 4 filter decreased Lp (a) by 70 % processing only 3,4 litres, however was less selective and limited by the loss of fibrinogen and other high molecular weight proteins. In patients with familial hypercholesterolaemia and Lp (a) elevation in a range of 80 - 120 mg /dl LDL-(immune) apheresis removed > 80 % of Lp(a) processing 6 litres of plasma whereas if 5 litres were processed a removal of 76 % was comparable to Liposorption. Neither whole blood perfusion (DALI, Fresenius) nor filtration applying the Kuraray LA 5 filter was able to reach the desired target values.

INTRODUCTION

Lipoprotein (a) is an LDL - like particle which was described as having an atherogenic [1,2,3, 4,5,6,7,8] and thrombogenic (9,10,11,12,13,14] potential. Whether Lp(a) increased the vascular risk only in combination with other risk factors such as increased LDL-cholesterol, low HDL-cholesterol, diabetes and others or could also be considered in a selective isoform as a genetically determined independent, isolated cause of atherogenesis [15,16,17,18,19,20, 21,22, 23,24,25,26,27] is under debate. Increased Lp (a) may be of pathogenetic importance for kidney diseases [27,28,29, 30,31,32,33,34], hypertension [35], diabetes [36, 37,38], stroke [39, 40] pulmonal hypertonia [41] and aneurismal disease [42].
With the development of Lp(a) - apheresis [43,44,45] the earlier claim, that there is "no treat-ment" for an elevated Lp(a) other than the elimination of additional risk factors is not valid any more. The term Lp(a) - apheresis should not be misused for other techniques also lowering Lp(a) (comparable to the confusion observed with the term LDL - apheresis). Procedures lowering both LDL - cholesterol and Lp(a) by 50 - 60 % may clinically not suffice as it may delay progression of atherogenesis rather than preventing it. Such prevention appears more likely to be obtained by Lp(a)-apheresis decrea-sing the pre-apheresis values about 80 - 90 % and obtaining post-treatment target values of 30 - 50 mg/dl with a better promise of optimal clinical efficacy. However, the rather rapid rebound needs to be taken into consideration.

STRUCTURE OF LIPOPROTEIN (a)

Lipoprotein (a) or abbreviated Lp(a) may be considered as an inherited, genetically determined special form of low density lipoprotein, which may explain the atherogenic potential. However differences in structure are obvious, as it also has a structural relationship to plasminogen, which may lead to an interference with the coagulation cascade.
The molecule consists of a core of cholesterol, phospholipids and apolipoprotein B 100 (apo b) which is linked to apolipo-protein a (apo a), a high molecular weight glycoprotein. Apo a is synthesized in the liver cells, but it is assumed that the binding with the LDL particle is an extracellular process. The way the particle is segregated is hardly known. The presence of apo a explains why it differs from LDL-Cholesterol. Apo a presents as an external "cringle " (cringle = Danish brezel) which surrounds the apo B core to which it is bound by a disulfide bridge. Lp (a) is a very heterogenous particle (up to 30 iso-forms) of different densities and molecular weights. The cringle structure of apolipoprotein A is homologous to plasminogen and enables the interference with the coagulation cascade.

AIM OF THE STUDY AND METHODS

We evaluated retrospectively 4 patients with selectively elevated Lp(a) and premature atherosclerosis treated under the following conditions:

• Initial range of Lp(a) between 80 - 120 mg/dl
• Application of the same procedure for each patient
  (Lp(a)-apheresis, LDL-(immune) apheresis, secondary plasma filtration)
  whereas the processed plasma volume varied from 3,4 - 6 litres.

All patients had a severe premature atherosclerosis with advanced coronary heart disease.
Also 8 patients with a combination of familial hypercholesterolaemia and elevated Lp (a) ranging from 80 - 120 mg/dl Lp(a) prior to apheresis and suffering from advanced coronary heart disease were evaluated if treated under the same conditions but with LDL-(immune) apheresis, liposorption, whole blood perfusion and secondary filtration though using a different filter.
All treatments were performed at weekly intervals (except for one patient with a selectively elevated Lp (a) who is treated every two weeks) attempting to reach Lp (a) post - treatment values of 30 - 40 mg/dl, The rebound was estimated calculating the average values after the treatments and comparing them with the average pre-treatment values.

RESULTS

DISCUSSION

The indication for the extracorporeal treatment of patients with a selectively elevated Lp(a) is under debate.
Lp(a) values exceeding the 75th percentile are at high risk for cardiovascular disease, demonstrated from studies such as PRIME, [46], ILSA [47] and others. This information is also supported from experimental data. As patients at high risk due to an elevated Lp(a), both as co- or independent risk factor, are with-out convincing drug therapy so far, extracorporeal elimination such as regular Lp(a) - aphe-re-sis is the therapy of choice and without alternative.
For all patients with a selectively elevated Lp(a) it is obligatory to eliminate additional risk factors such as smoking, hypertonia, obesity and others to be eliminated. However this is no treatment but prerequisite. As we have seen patients with selectively elevated Lp (a) values of more than 250 mg/dl without premature atherosclerosis we recommend that such patients remain under cardio- angiological control once per year but without treatment. If the development of premature atherosclerosis with clinical relevance can be demonstrated during the observation period, early treatment should be initiated even if no further risk factors can be found. It is beyond debate that patients characterised from a selectively elevated Lp (a) e.g. > 80 mg/dl, premature atherosclerosis without further risk factors and particularly if clinically symptomatic with an early vascular disease (e.g. myocardial infarction underneath 35 - 40 years of age) must be treated with Lp (a) apheresis.
For patients with familial hypercholesterolaemia in combination with elevated Lp (a) also no treatment alternative exists, after diet and cholesterol lowering medications have exhaustively been applied.
The thrombogenic potential if of clinical relevance for such patients may also be taken into consideration.
Whether the lack of controlled trials providing for final evidence of the clinical value of an extracorporeal elimination of Lp(a) in severely sick patients and patients at high coronary risk appears to be a formality for reimbursement or justifies Lp (a) apheresis with all consequences for the maintenance of an optimal quality of life and life expectancy may not only be considered as a problem of generalised consideration and bureaucratic formalism but needs also an individualised, thoughtful decision as an issue of medical ethics.
In analogy of our 26 years experience with the original LDL - apheresis and the survival of patients under optimal treatment conditions we favour post-treatment target values of 30 - 40 mg/dl rather than referring only to a decrease expressed in percentage as this approach appears to promise a better or even an optimal clinical efficacy. Nevertheless, if such percentage is taken as a measure it should exceed a decrease of at least 70 %. However, the rather rapid rebound needs also to be taken into consideration.
For patients with a selectively elevated Lp (a), the choice of the optimal treatment technique depends on the initial level of Lp (a). Lp (a) apheresis is the most potent elimination procedure which guarantees optimal post-treatment values, but needs the procession of higher plasma volumes, whereas other techniques such as plasma differential filtration eliminate other plasma components as well and have a limited capacity suitable for the treatment of patients with lower Lp(a) values (underneath 80 mg/dl).
FH patients with an additional elevated Lp (a) are more difficult to treat, as LDL-apheresis columns if used in a repetitive cycling approach may obtain optimal post-treatment values of LDL-cholesterol but only suboptimal post-treatment Lp (a) values. Thus technical considerations for an optimal decrease of both risk factors for the best treatment of these patients are necessary.
As 30 mg/dl are considered as "normal" one should consider this value as target for an optimal patient treatment rather than restricting oneself to a limited percentage of Lp(a) elimination (e.g. 60 %). The treatment should completely eliminate Lp (a) as the risk factor, if it is technically possible, to maintain, an optimal quality of life and halting the progress of premature atherosclerosis for an optimal survival.
This evaluation cannot replace a controlled trial, particularly as it restricts itself to a retrospective approach and the comparison of different treatment techniques. Also, it comprises only a limited number of comparable procedures. Nevertheless, it contributes to the selection of the most efficient and most economic elimination procedure.
Variations of the measurement procedures [48,49,50,51,52, 53] with new insights into the importance of the size heterogeneity together with other issues raised again discussions whether Lp (a) increased the vascular risk only in combination with other risk factors such as increased LDL-cholesterol, low HDL-cholesterol, diabetes and others or could also be considered as a genetically determined independent, isolated cause of atherogenesis. Such discussion is directly related to the indication for extracorporeal Lp(a) lowering therapy.
Numerous procedures have been applied to estimate the efficacy of extracorporeal cholesterol lowering therapy. The most convincing evidence is the survival of patients under long term treatment. Patients with selectively elevated Lp (a) are of special interest.
One of the 4 patients is now under regular therapy for 15 years without obvious signs of progression, whereas the other 3 patients are treated only for 1 -1/12 years so far and do not yet allow to draw any conclusion. Thus, a controlled trial using Lp (a) apheresis for patients with Lp (a) concentrations of more than 80 mg/dl is desirable. However, due to the complexity of the problem one should not underestimate the problems of designing such trial.

CONCLUSIONS

1. Lp (a) - apheresis as developed from Prokovski at the National Academy of Medical Sciences at Moscow allows for the most efficient elimination with a decrease of at least 80 % of the pre-treatment Lp (a) level. However, due to the contents of apoprotein B Lp(a)-apheresis also eliminates LDL-cholesterol to some extent.
2. LDL - apheresis (immune apheresis) and Liposorption appear to have a capacity of lowering about 76 % of the initial value in patients with both FH and elevated Lp (a).
3. Filtration using the Kuraray LA 4 filter (in combination with centrifugal primary separation) allows for a decrease of 70 % whereas whole blood adsorption is limited to a decrease of only 65 %. However, it has to be taken into consideration, that plasma differential filtration is only semiselective, removing other high molecular plasma components (e.g. fibrinogen about 65% and total protein about 20 % of the pre-treatment value) together with Lp (a) and that the extent of treatment is limited from the loss of fibrinogen.
4. The decrease of Lp (a) correlates with the plasma volume processed.
5. As Lp (a) immune - apheresis uses repetitive cycling it allows for processing virtually indefinite volumes and due to the reuse it is most economic. Thus, it can be recommended for the treatment of Lp (a) values exceeding 80 mg/dl.
6. A controlled trial applying Lp (a) apheresis to patients with Lp (a) values of more than 80 mg /dl is most desirable, as the data available so far strongly support the usefulness of extracorporeal Lp (a) lowering therapy in patients with selectively elevated Lp (a), whereas an improvement of the currently available technologies appears to be necessary for patients with familial hypercholesterolaemia (especially homozygous patients) and simultaneous Lp (a) levels beyond 100 mg/dl.

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History

Definition of LDL-Apheresis

Fig. 1	Fig. 2
Primary separation system	Secondary separation system

PRINCIPLE OF LDL - APHERESIS:

Secondary Separation using therapeutic Affinity Chromatography

Carrier material +	Ligand =	Adsorption
(Sepharose)	(Sheep antibody against Apolipoprotein B)	(of Apo-B containing Particles e.g. LDL-Cholesterol) *

* Other Apoprotein B containing particles: VLDL = Very low density lipoprotein,
IDL = Intermediate density lipoproteins, Lp(a) = Lipoprotein (a)

Summary of achievements during the period of 1981 - 2007

• Up to 2007 more than 60.000 treatments were performed in Cologne, world-wide more than 400.000
• the therapies were performed as outpatient treatments


• so far no severe side effects were seen (at present approximately 4 % of minor undesired reactions) especially


• no anaphylactic shocks
• no transfer of any patient into a hospital as complication of any of the treatments
• no artificial excess to the circulation necessary, even under long term therapy (according to our experience in apheresis an artificial excess to circulation is not necessary, thus avoiding the associated complications e.g. due to shunts which, under these circumstances, may well be considered as medical malpractice).
• extension from originally 10 homozygous FH-patients to an increasing number of heterozygous patients without treatment alternative (more than 30 patients currently being treated in Cologne)
• improvement or maintenance of the quality of life
(e.g. decrease of the number or severity of angina pectoris attacks up to their complete elimination
• a prevention or delay of cardiological or cardiosurgical interventions (PTCA or bypass surgery) depending on the compliance of the patients or the existence of additional risk factors for instance LP(a)
• positive influence on morphological - clinical parameters
• in general complete regression of xanthomaes, xanthelasmae
• regression (as shown by radiological procedures) of coronary heart disease in young patients of high risk (up to at least 18 years of age, probably up to a higher age)
• secondary prevention (delay of progression and under optimal target values also a hold of progression) in the elderly
• primary prevention up to 18 years of age possible
• prolongation of life expectancy substantially in homozygous patients (so far no athero-sclerosis related death in 25 years)
• corresponding experience also with heterozygous patients according to the current data and experience
• impressive survival of patients with end-stage-disease
• transfer of the technological principal of therapeutic affinity chromatography to other applications(e.g. Digoxin-, Ig-, Lp(a)-Apheresis).

Survival as proof of efficacy

Fig. 4	Fig. 5
Primary separation system	Secondary separation system

1. The nomenclature is incorrect. Specific, semi-selective and selective procedures are mixed up, though the efficacy of LDL-C elimination of different technologies is considerably divergent and may have clinical consequences. Though the clinical importance is often of limited value, however since they are considered to be guidelines they are generally used for formal judgement.
2. The lowering of 60 % of the initial value of LDL-cholesterol is considered to be suffi-cient in these guidelines. Obviously a nomination of target values was not considered to be necessary.
3. Quality control measures and thus the insurance of clinically relevant long term results was not being taken care of and should be included.
4. It is assumed, that a certain group of physicians is automaticly qualified and thus permitted to treat such patients. However, their competence as related to apheresis technology or to the knowledge and the experience with the treatment of cholesterol lowering (and other metabolic diseases) may be doubtful.
5. The same holds true for boards controlling the indication. This becomes obvious if the indications for the treatment of the patients with type III, IV and V according to Frederickson and the role of additional risk factors (e.g. low HDL-cholesterol, increased LP(a)) which must not necessarily be treated with LDL-Apheresis or some analogous procedures are to be decided. The specific competence especially of members of such public service should be transparent and thus available for the judgement of metabolic specialists especially in the field of cholesterol metabolism.

1. The different procedures used to lower LDL-cholesterol should be evaluated and considered differently according to their specificity, their efficacy per single treatment and their economy.
2. Target values should be introduced and replace the general recommendation of a decrease of 60 %.
3. Quality control procedures are necessary to improve the safety and the clinically available aims, such as regression, decrease of progression or complete halt of progression. The establishment of individual risk profiles prior to the first therapy is according to our experience a must.
4. According to the opinion of our patients a more detailed determination of the qualification of the treating physician is pre-requisite for the permission to perform LDL-cholesterol decreasing therapies. The establishment and promotion of centres of competence may well increase the efficacy and improve the cost-efficacy relation.
5. The selection and the competence of the so named "competent commission" of the board of physicians deciding upon the indication for LDL-Apheresis should be transparent. A definition of the competence of the board members appears to be obligatory.
6. In case treating physicians are supported from industry they should be obliged to reveal their relations to industrial sponsors.
7. An individual judgement for the treatment indication should in special cases be possible.

1. Reduction of the LDL-cholesterol increase after therapy.
2. Optimation of the post-treatment values and values in between therapy.
3. Abbreviation of the LDL-Apheresis procedure.
4. Additional pleiotrophic effects, being under debate.

1. A diminuition of 60 % of the initial cholesterol does not represent the nowadays technical possibilities of a repetitive-cycling treatment procedure.
2. The increase of the LDL-cholesterol after apheresis should be taken more into consideration and related to the technical procedure.
3. End-stage-disease-patients can, if an aggressive lowering of the LDL-cholesterol is applied, experience an unexpected improvement of the quality of life and a remarkable prolongation.
4. According to newer insights drug therapy alone already favours a more intensive treatment (1, 3, 16, 22).

• The removal of modified LDL-cholesterol
• The influence on the rheology
• The influence on the membranes of blood cells mainly of erythrocytes and platelets
• The influence on the endothelium (induction of blood vessel dilating factors and cytokines)
• The anti-inflammatory effect.

1. The control of the target values (laboratory data prior to and after each treatment)
2. The documentation of the type and frequency of side effects as well due to the apheresis as the cholesterol lowering additional medication
3. The technical documentation for instance of
   · the treatment technique (separation system, adsorbers, operators) and
   · the processed blood- /plasma-volume,
   · the flow rates, alarms etc.
4. The detailed pre-treatment prescription of the responsible physician and the documenta-tion of the responsible operator
5. The control of the patient data, interim history and all necessary forms
6. Print outs of protocols and graphics of the treatment data
7. Administration of safety certificates, validations and charges
8. Statistical evaluations
9. Support of the treatment reports
10. Control of storage materials and purchasing
11. Control of economy and accounting

Fig.6

Re-use cost development of repetetive-cyclic adsorption columns: Exponential decrease of material cost during re-use (yellow line) as compared to constant costs of single use systems (red line).

• Resuscitation after myocardial infarction due to progressed coronary sclerosis
• No further therapeutic cardiological (e.g. stents) or cardiosurgery (e.g. 3 or 4 bypass surgeries) or analogous angiologic surgical procedures
• Minimal working exercise (e.g. underneath 25 Watt)
• More than 3 angina pectoris attacks per day at rest without physical challenge in spite of maximal antianginal therapy
• Optimal treatment or exclusion of other risk factors
• Proof of far advanced pathological coronary morphology
• Exhaustive application of all maximal possible cholesterol lowering diet and drug therapy especially applying different drug combinations.

1. The prolongation of patients survival mainly of those with homozygous familial hyper-cholesterolaemia without treatment alternative is among many other proofs of efficacy the strongest argument for the efficacy of LDL-Apheresis.


2. Further optimation are possible such as improvement of the guidelines, definition of target values, consideration of sufficient competence for treating physicians and examination boards, quality control, mechanisms, development of industry competence centres etc. These improvements lead to an increase of the quality of life and a relativation of hypercholesterolaemia as risk factors and may also lead to increased consideration and treatment of other simultaneously present risk factors. This should lead to the need of an extensive maximal patient treatment, which can best be performed in industry independent competence centres.


3. Further improvement of the economy is possible due to the use of optimal technical devices and the reuse of suitable absorbers and new technical development.


4. If a medical and technical optimation is desired and an improvement organisation for the treatment of familial hypercholesterolaemia is desired, the discussion of the collected experience and results is an absolute necessity after we were prevented from performing a controlled trial 20 years ago (1).

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