LDL-apheresis: questions for the future

Transfusion Science 20 (1999) 43±47

LDL-apheresis: questions for the future E. Bruckert Prevention of Cardiovascular Diseases, Endocrinology Department, H^ opital Piti e-Salp^ etri ere, Paris, France Received 11 September 1998; accepted 1 November 1998

1. Introduction LDL particles constitute the predominant form of transport of cholesterol towards tissue. It is now obvious that LDL particles are one of the major causative factors in the development of coronary heart disease (CHD). Numerous studies have established the relationship between plasma LDLcholesterol levels and coronary heart disease [1±3]. Perhaps the most convincing evidence that these lipoproteins are causative factors in this disease is the genetic disorder, familial hypercholesterolemia. Homozygous patients develop massive LDL concentrations and frequently die within the second decade of life from complications of atherosclerosis. Furthermore, recent trials with the HMGCoAreductase inhibitors showed that the reduction of LDL-cholesterol levels was associated with a 30% decrease in coronary events [1,3]. LDL particles play a major role in the di€erent stages of the development of atherosclerosis. One of the earliest events in the formation of plaques is the focal accumulation of circulating LDL within the subintimal space. Shortly after, monocytes take up LDL particles and subsequently take the appearance of foam cells. Elevated concentrations of LDL-cholesterol are also associated with a variety of abnormalities including increased platelet aggregation, endothelial dysfunction and impairment of angiogenesis. Consequently LDL apheresis may delay the development and progression of atherosclerosis and may also be e€ective at a later

stage. It has been shown that LDL apheresis was associated with an improvement in endothelial dysfunction [4]. Therefore, a huge body of evidence shows the central role of LDL in CHD and the necessity to treat hypercholesterolemic patients. A majority of hypercholesterolemic patients are adequately treated by diet therapy alone or associated with drug therapy. However some patients are still candidates for a more aggressive approach, especially among those who have a severe familial disorder. In this short review, the accepted indications, the ecacy of the technique, the new indications and the questions and limitations of the procedure will be discussed. Since the ®rst plasmapheresis for homozygous familial hypercholesterolemia, in 1967, years of intensive work have led to an easy and ecient technique for selectively removing the atherogenic LDL particles from the plasma. Several LDL apheresis methods have been developed, including: (1) columns containing immobilized anti-apolipoprotein B antibodies, (2) heparin-induced extracorporeal LDL precipitation, (3) columns containing dextran-sulfate and (4) the ®ltration technique. On average LDL apheresis is associated with a dramatic decrease in LDL-cholesterol [5,6]. Speci®city of the procedure di€ers depending on the technique. For example, globulin levels decrease by 50±60% with plasma exchange and is also observed with the ®ltration technique (See Table 1).

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E. Bruckert / Transfusion Science 20 (1999) 43±47

Table 1 Ecacy of LDL apheresis and the less speci®c technique which is plasmapheresis Technique

Percentage decrease LDL-c

HDL-c

Globulins

Fibrinogen

Plasma exchange Immuno-absorption HELP Dextran-sulfate Filtration

40±63 44±82 65±74 60±64 53±63

55±60 14±40 10±37 0±17 25±30

50±60 3±5 0±9 20±22 39±45

41±76 25±32 51±65 10±15 30±35

Selective technique removes LDL and to a lesser extend HDL particles from the plasma. They are also associated with a diminution of ®brinogen which is a well-known cardiovascular risk factor. Adapted from Keller C., Atherosclerosis, 1991.

All these currently available systems can only eliminate LDL from plasma and therefore require a primary step of separating the blood cells and plasma. The new DALI system has the ability to separate LDL from whole blood. This technique reduces the duration of each session [7]. The LDL apheresis technique should be considered in the following conditions: (1) in patients with very high levels of cholesterol; that is to say the homozygous form of familial hypercholesterolemia. These patients lack LDL-receptors and do not exhibit a signi®cant decrease of plasma LDL-cholesterol with the available drugs and patients with CHD and high levels of cholesterol because of a lack of ecacy of the drugs or because of unacceptable side e€ects of the medication. There are three major reasons to treat homozygous patients: (1) their cardiovascular prognosis is very bad, (2) drugs are ine€ective and surgical procedures such as partial ileal bypass, portocaval shunt and liver transplantation have been associated with considerable morbidity, and (3) LDL apheresis decreases LDL-cholesterol and has been shown to be associated with improved life expectancy. As an example, we have been treating a young patient with severe homozygous familial hypercholesterolemia for more than 10 yr. This boy presented with planar xanthomas and cholesterol above 1000 mg/dl. A variety of hypolipidemic drugs were shown to be ine€ective in this boy. He is presently treated weekly by LDL apheresis and is now 30 years old. A recent coronary angiogram was shown to be normal.

Thirty-four patients are currently being treated in our group. Seventeen have homozygous familial hypercholesterolemia. Most of these patients displayed a serum cholesterol level, before any treatment, above 800 mg/dl. Among these patients, 12 are children under eighteen. The youngest is 5. The technique is not easy to handle in the youngest patients. However, we have shown that the treatment is associated with a stabilisation of some coronary atherosclerotic plaques in these patients [8]. Thirteen have coronary heart disease and are under 60 years old. They also presented with a plasma LDL-c level above 250 despite hypolipidemic drugs. Among these patients, 11 have heterozygous FH. One has combined hyperlipidemia and non-insulin-dependent diabetes. There is no general agreement on the threshold level of LDL above which patients should be treated. In our group we treat patients with LDL above 250 mg/dl despite adequate dietary treatment and a maximal tolerated combination of hypolipidemic drugs. One patient has intermittent claudication, severe combined hyperlipidemia and myopathy (Mc Ardle's disease). One patient under ®fty has severe CHD. He has no other risk factor, and only a moderately elevated LDL but he has a Lp(a) plasma level above 200 mg/l. Two patients have Refsum's disease. LDL apheresis may be of use as a long-term treatment as well as short term treatment. It may be considered as a long-term treatment in the following conditions: (1) Aggressive therapeutic approach for patients having severe coronary heart disease.

E. Bruckert / Transfusion Science 20 (1999) 43±47

(2) In addition to lowering LDL-cholesterol, removal of Lp(a) in patients with coronary heart disease and high levels of Lp(a). (3) Removal of phytanic acid in patients with Refsum's disease. This disease is characterized by the accumulation of phytanic acid in blood and tissues. The manifestations are retinis pigmentosa, peripheral neuropathy, cerebellar ataxia and other less constant features such as nerve deafness and ichthyosis. (4) Removal of very long-chain fatty acids in patients with the adult form of adrenoleucodystrophy. As a short-term treatment it may be useful to treat patients with: (1) Secondary hyperlipidemia such as nephrotic syndrome (2) Patients with pancreatitis and very high levels of triglycerides (3) Prevention of restenosis after angioplasty A more aggressive approach to lowering LDLcholesterol may be of value since there is increasing evidence that dramatic lowering of LDL is bene®cial. Furthermore, the technique may have additional e€ects. It removes LDL particles and also Lp(a). The technique removes ®brinogen and may also cause LDL to be more resistant to oxidation. There are at least four reasons to consider apheresis in patients with very high plasma Lp(a) levels: (1) Lp(a) is a well-known risk factor for CHD. It acts synergistically with high levels if LDLcholesterol. (2) Statin therapy may increase plasma Lp(a) levels especially in patients with a high baseline level. (3) Drugs which lower Lp(a) are not well tolerated. (4) Apheresis decreases Lp(a) levels by about 50%. The diminution of Lp(a) parallels the decrease in LDL particles. Niacin and neomycin decrease Lp(a) levels by 30%. However, they are not well tolerated and most of the patients to whom these drugs are given are not compliant. Li®brol and analogs of thyroxine are not yet available. Estrogen therapy is associated with a signi®cant decrease in Lp(a) levels but the treatment cannot be recommended

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for men. Although there is still a necessity to prove the usefulness of decreasing Lp(a) levels in terms of clinical events, it is of interest to note that this therapeutic approach may reduce the occurrence of restenosis. What are the questions and the limitations for the future? (1) Is it bene®cial to decrease Lp(a) levels in terms of coronary event and this question is particularly important when LDL (LDL)-c levels are low? (2) Does the decrease in TG levels improve the prognosis of patients who have pancreatitis? (3) Does the decrease in phytanic acid levels improve the neurologic symptoms in Refsum's disease? (4) Is it bene®cial to decrease ®brinogen level? (5) Has the intermittent action of the treatment the same bene®t as sustained decrease in LDLcholesterol by conventional drug therapy? (6) Do non-speci®c reductions in blood proteins, vitamins or oligoelements have signi®cant clinical consequences? To answer these questions it is of major importance to undertake new trials with clinical endpoints. Although the treatment has proved its ecacy in decreasing LDL-cholesterol and was shown to be associated with a regression of coronary atherosclerotic plaques, there are limitations to extending the use of the technique. One of these limitations is the cost of the treatment which remains very high (about 7500 FF per session with the more speci®c techniques). Table 2 Reductions in blood vitamins

Vitamin E Before After Beta-carotene Before After

Treatment for 3±24 months

Treatment 24±108 months

4.7‹0.6 5.2‹0.7

4.3‹1.1 5.1‹1.5

0.04‹0.02 0.06‹0.03

0.05‹0.03 0.06‹0.02

Vitamin E/cholesterol and betacarotene/cholesterol ratios for patients treated by LDL apheresis. Results are given according to the treatment duration. Adapted from Ref. [10].

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E. Bruckert / Transfusion Science 20 (1999) 43±47

Table 3 Non-speci®c reductions in blood oligoelements Selenium * Selenium ** Seleno-protein Extracellular Gluthatione peroxydase (GP) Erythrocyte cellular GP

Before apheresis

After apheresis

Percentage decrease (p)

0.88 ‹ 0.32 0.73 ‹ 0.21 1.11 ‹ 0.17 352 ‹ 75 26 ‹ 4

0.58 ‹ 0.20 0.42 ‹ 0.15 0.51 ‹ 0.17 303 ‹ 72 26 ‹ 4

34% 42% 54% 14% NS

(<0.001) (<0.001) (<0.001) (<0.001)

Selenium, Seleno-protein, Gluthatione peroxydase (GP) activities in hypercholesterolemic patients treated by LDL apheresis. * n ˆ 15, Lancet, 1994, 343: 1160. ** n ˆ 13, Clin Clim Acta 1995, 204: 209.

The second limitation has to do with the increasing potency of the new hypolipidemic drugs. Atorvastatin which is a potent HMGCoA-reductase inhibitor may decrease LDL-cholesterol up to 60% and has also been shown to decrease LDLcholesterol in the homozygous form of familial hypercholesterolemia. Few studies are available. For example there are only ®ve studies with angiographic end-points, only two of them being randomized. Since vitamin E and other lipophilic antioxidants are transported via the LDL, the technique may also lead to a decrease in these vitamins [9±12]. However, we did not ®nd any modi®cation in the ratio of vitamine E to cholesterol in patients treated by LDL apheresis (Table 2). We have recently shown that LDL apheresis was associated with an immediate 33% decrease in selenium (Table 3). Patients treated repeatedly by the technique exhibit lower levels of this oligoelement. Despite the removal of antioxidant associated with the LDL particles and our ®nding that the use of dextran-sulfate as an adsorbent decreases selenium in patients with FH, we were not able to ®nd any increase in LDL oxidative susceptibility in patients currently treated by the technique. On the contrary, we con®rmed previous results published by Napoli et al and found that the LDL of homozygous patients were more resistant to oxidation. We also showed that the susceptibility of oxidation varies among the subspecies (data not published). In conclusion the number of patients treated by LDL apheresis will probably not increase dramatically because of the lack of studies showing major bene®t in terms of clinical events and because of the cost of the procedure. However the

technique may be of value in new indications including patients with Lp(a) secondary hyperlipidemia [13] or neurologic disorders with tissue accumulation of abnormal fatty acids. References [1] Shepherd J et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333:1301±1307. [2] Smith GD, Song F, Sheldon TA. Cholesterol lowering and mortality: the importance of considering initial level of risk. BMJ 1993;306:1367±1373. [3] Scandinavan simvastatin survival study group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the scandinavian simvastatin survival study (4S). Lancet 1994;344:1383±1389. [4] Aengevaeren WRM, Kroon AA, Stalenhoef AFH, Uijen GJH, van de Werf T. Low density lipoprotein apheresis improves regional myocardial perfusion in patients with hypercholesterolemia and extensive coronary heart disease. JACC 1996;28:1696±1704. [5] Dairou F, Assogba U, Bruckert E, De Gennes JL, Tru€ert J. Ecacite biologique des LDL aphereses dans les hypercholesterolemies majeures. Ann Med Interne 1994;145(5):328±332. [6] Dairou F, Rottembourg G, De Gennes JL, Assogba U, Bruckert E, Jacobs C, Tru€ert J. Comparaison des traitements des formes severes d'hypercholesterolemie familiale par echange plasmatique total et epuration selective des lipoproteines de basse densite (LDLapherese). Presse medicale 1988;33(17):1679±1682. [7] Bosch T, Schmidt B, Blumenstein M, Gurland HJ. Lipid apheresis by hemoperfusion: in vitro ecacy and ex vivo biocompatibility of a new low-density lipoprotein adsorber compatible with human whole blood. Arti Org 1993;17:640±652. [8] Klein JM, Drobinski G, Bruckert E, Dairou F, Thomas D, De Gennes JL, Grogosgeat Y. Results of serial coronary angiography in patients with homozygous familial hypercholesterolemia. European Heart J 1988;9:1067±1073.

E. Bruckert / Transfusion Science 20 (1999) 43±47 [9] Jaudon M-C, Assogba U, Bourely B, Dairou F, Bruckert E, Delattre J. Selenium de®ciency in hypercholesterolemic patients treated by LDL apheresis. Lancet 1994; 343:1160. [10] Assogba U, Lepage S, Bruckert E, Bonnefont-Rousselot D, Dairou F, DE Gennes JL, Delattre J. Blood antioxidants (vitamin E and beta-carotene) in long-term low density lipoprotein apheresis. Clin Chim Acta 1995;235:147±157. [11] Persson-Moschos M, Bonnefont-Rousselot D, Assogba U, Bruckert E, Jaudon MC, Delattre J, Akesson B. Prefer-

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ential depletion of selenoprotein P in hypercholesterolemic patients treated by LDL-apheresis. Clin Chim Acta 1995;204:209±212. [12] Dejager S, Bruckert E, Chapman MJ. Diminished oxidative resistance of low density lipoprotein subspecies in combined hyperlipidemia. J Lipid Res 1993;34:295±308. [13] Faucher C, Albert C, Beau®ls H, Jouanneau C, Dupouet L. Remission of a refractory nephrotic syndrome after low-density lipoprotein apheresis based on dextrant sulphate adsorption. Nephrol Dial Transplant 1997;12:1037± 1039.