CHANGE OF PARADIGMAS
IN LDL -APHERESIS
H ELMUT B ORBERG
Presentation helt on the European Haemapheresis Congress, Praha, September 2003
GERMAN HAEMAPHERESIS
MAARWEG 165
D - 5 0 8 2 5 KÖ L N
CENTRE
1. Introduction
In 1981 the until now only specific LDL – elimination system was first taken into clinical
practice. The name LDL – apheresis was introduced for this technique, however, the use of
this name was increasingly perverted from procedures eliminating other plasma proteins,
among them also LDL – cholesterol.
2. Technologies
The original technique consisted of one single column of Sepharose 4b Cl using a sheep antiApoprotein B as antibody. The LDL elimination capacity of this column was approximately
50 – 60 % which turned out to be not sufficiently effective for patients with high initial values
of LDL – cholesterol, e.g. in homozygotes. Thus repetitive cycling within one treatment was
developed, allowing for a virtual indefinite capacity of elimination during one treatment.
However, as the reuse within one treatment also permits the reuse from one treatment to the
other, the automated reuse was successfully introduced also for economic reasons. Thus, the
magnitude of the elimination representing the medical value and the economy of the therapy
became the major determinants of LDL – elimination therapies.
Disposable, single usage devices developed subsequently, became fashionable but did frequently not fulfil the medical requirements for an optimal patient treatment or the economic
optimisation. They reproduced our experience obtained already in 1981. Due to the loss of
normal plasma constituents and the thus limited decrease of LDL – cholesterol they are
technically considered as second line approaches (precipitation, filtration, whole blood adsorption), applicable for limited time periods or rheological purposes, whereas reusable techniques with repetitive cycling and a capacity allowing for the removal of >80 % of the initial
LDL - cholesterol remain the first line procedures in terms of efficacy and economy.
3. Target values
In 1981 and 1982 the lack of experience, the uncertainty about the extent of the necessary
LDL – cholesterol reduction and the initial R + D problems defined target values of 300 – 350
mg /dl total cholesterol after treatment pleasing. The technical improvement allowed for a
further decrease to 200 – 250 mg/dl during the next 2 years, followed from the demand for
lower post-treatment values (150 – 200 mg/dl total cholesterol) subsequently. The
disappearance of xanthomae and angina pectoris attacks, the improved quality of life, the
diminished number of PTCAs and bypass operations, the prolonged survival not only of
homozygotes observed over a period of now 22 years and the survival of patients with end
stage atherosclerosis accompanied from a similar experience with aggressive cholesterol
reduction in patients treated with cholesterol lowering drugs introduced the demand for posttreatment target values of not more than 80 - 100 mg /dl total cholesterol or correspondingly
50 – 60 mg / dl LDL – cholesterol. If further decreases can be achieved, the must be taken
into consideration. Repetitive cycling techniques generally achieve these results.
4. Additional cholesterol lowering drug therapy
For the majority of patients with familial hypercholesterolaemia undergoing LDL – apheresis
the treatment was indicated as the response to cholesterol lowering drug therapy did not meet
the necessary target values. Drug therapy modifying the increase of cholesterol from one
apheresis treatment to the other, may be of benefit for these FH patients even in small
tolerated dosages only. Whereas in 1981 fibrates and bile acid binding drugs were mainly
available, statins with or without combination of bile acid binders resemble the current
standard of cholesterol lowering drug therapy. More recently ezetimibe was introduced as an
additional therapeutic option allowing for a further decrease of 10 – 20 %. Whereas the
pleiotropic effects of statins are also of importance, it can not be excluded that LDL –
apheresis may exert corresponding effects beyond that of an LDL – cholesterol elimination.
New cholesterol lowering drugs are coming up. As they will be applied in a rather complex
metabolic situation (as compared to monotherapeutical evaluations), an individualised,
industry independent testing is necessary. The improvement of drug therapy must in general
not lead to an extension of treatment intervals but to an optimisation of apheresis therapy.
5. Clinical aims
In the early eighties a retardation of the progression of atherosclerosis in the majority of the
FH patients under apheresis therapy appeared to be sufficiently appealing. However, the
demonstration of regression in such patients and the increasingly better results with optimised
target values promoted the idea that a halt of the progression rather than a delay of premature
atherosclerosis with all the medical benefits for the patient and the economical advantages for
the health economy must be the clinical aim. The treatment principle appears quite simple: A
patient suffering from a risk factor such as elevated LDL – cholesterol has to eliminate it –
completely and not partially, if the best medical and economic result shall be achieved. The
complete elimination of the risk factor LDL-cholesterol should not only provide for a normal
quality of life and a normal life expectancy also eliminating expensive cardiological or
cardiosurgical interventions being the standard in earlier years without apheresis. However,
these expectations are limited, especially in homozygous FH patients if additional risk factors
such as lack of compliance with irregular apheresis treatments, increased Lp(a), low HDL –
cholesterol, smoking, hypertonia, diabetes weight problems, lack of exercise etc. do exist. It is
our firm believe that based on our long term experience with LDL – apheresis since 1981
such risk factors determine the fate of the patient at least as much if not more than a well
treated LDL – cholesterol. Thus, the assessment of the overall risk with subsequent
counselling of the patient
6. Quality
Whereas controls of efficacy serving scientific interests were established with the introduction
of LDL-apheresis, clinically oriented quality controls were introduced later on, but so far only
in leading centres. Quality controls must not only include the control of clinical-chemical preand post-treatment data but also regular clinical examinations and consultancy services for the
patient. After it turned out that the medical quality of extracorporeal LDL – elimination therapy appeared to be debatable if performed from specialists experienced only in apheresis technology, the discussion how to optimise the treatment approach was initiated. It is clear so far,
that this topic can not be left to the responsibility of the manufacturers. Guidelines from industry independent cholesterol specialists, in collaboration with apheresis specialists qualified
in LDL – elimination technologies, cardiologists and angiologists should be established to
provide for an increase of the treatment quality which is urgently needed. The current German
guidelines though recently revised are only in parts acceptable and behind the current standard
of experience. It may also be useful to establish and support centres of competence, which are
independent from industrial interests, allow for competition and transparency of not only the
treatment approaches.
7. Economy
With shrinking resources of the public health systems in all European countries the economical consideration of haemapheresis therapies gains importance. Reusable systems applied for
more than 22 years without remarkable side effects are most economic if the break even point
of a centre is overcome. In the early eighties we were glad if a reuse of up to 50 treatments
was obtained. Nowadays a minimum of 80 applications is feasible and up to 200 applications
have been demonstrated in individual patients.
It is also an economical difference whether a double filtration system is used once a day or the
multi – purpose blood cell separator used for LDL – apheresis can equally be applied up to 3
times during the same day for platelet preparation, stem cell procurement or cytapheresis
therapies. The same holds true for the multi – purpose automated adsorption desorption
device.
8. Summary
1. As compared to 1981 the magnitude of the LDL – lowering capacity of extracorporeal
techniques has considerably increased. Technologies which do not allow for a decrease of
2.
3.
4.
5.
6.
at least 80 % of the initial LDL-cholesterol value such as disposable, single use
procedures, should be considered as second line technologies.
In earlier years the treatment efficacy was mainly determined from the capacity of the
technique applied and limited. As the repetitive cycling technology permits optimal low
post – treatment target values, values of not more than 80 - 100 mg /dl total cholesterol or
correspondingly 50 – 60 mg / dl LDL – cholesterol after apheresis are now considered to
be optimal. If further decreases can be achieved, the must be taken into consideration.
Additional cholesterol lowering drug therapy, if applicable and tolerated, has considerably
improved the results of LDL-elimination therapy. The addional effects must not be used to
extend the treatment intervals but to optimise the treatment efficacy. Pleiotropic effects
may improve the clinical efficay of LDL-cholesterol removal.
Instead of achieving a retardation of the progression of atherosclerosis, which appeared to
be acceptable in earlier years, the clinical target has now changed to a complete halt of the
progression rather than a delay of premature atherosclerosis. However, the efficacy of the
elimination of LDL – cholesterol as a first order risk factor is limited, if other risk factors
are present. Thus the therapeutic strategy has changed from the exclusive consideration of
LDL-cholesterol to an overall risk assessment of the patient.
Whereas controls of the treatment efficacy serving scientific interests were used during
the introduction of LDL-apheresis, clinically oriented regular quality controls of clinical –
chemical and clinical data are now available. The current available LDL-elimination
guidelines need to be updated and centres of excellence and competence are necessary to
assure industry independent standards.
Whereas in earlier years the need for apheresis techniques for patients without treatment
alternative were most important, the technical improvement and the shrinking resources of
the public health systems require an increased cost consciousness.
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References for further reading may be requested from the author