Low-Density Lipoprotein Apheresis for the Treatment of Refractory Hyperlipidemia

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Subspecialty Clinics: Endocrinology, Metabolism, and Nutrition

Low-Density Lipoprotein Apheresis for the Treatment of Refractory Hyperlipidemia ADRIAN VELLA, MD; ALVARO A. PINEDA, MD; AND TIMOTHY O’BRIEN, MD, PHDgery The advent of treatment with 3-hydroxy-3-methylglutaryl coenzyme A inhibitors has meant that, with a combination of diet and drug therapy, adequate control of serum cholesterol concentrations can be achieved in most patients with hypercholesterolemia. However, some patients, primarily those with familial hypercholesterolemia (FH), may require additional therapy to lower their cholesterol levels. In recent years, low-density lipoprotein (LDL) apheresis has emerged as an effective method of treatment in these patients. The criteria for commencement of LDL apheresis are LDL cholesterol levels of 500 mg/dL or higher for homozygous FH patients, 300 mg/dL or higher for heterozygous FH patients in whom medical therapy has failed, and 200 mg/dL or higher for heterozygous FH patients with documented coronary disease and in whom medical therapy has failed. In addition to cholesterol low-

ering in patients with FH, other indications for LDL apheresis are emerging. These include its use in the treatment of graft vascular disease in patients receiving cardiac transplants as well as in the treatment of certain glomerulonephritides. This review examines the role of LDL apheresis in the management of lipid disorders and the evidence available to support its use in clinical practice. Mayo Clin Proc. 2001;76:1039-1046 ACEI = angiotensin-converting enzyme inhibitor; apo B = apolipoprotein B; DFPP = double-filtration plasmapheresis; FH = familial hypercholesterolemia; HDL = high-density lipoprotein; HELP = heparin extracorporeal LDL precipitation; HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A; LDL = low-density lipoprotein; NCEP = National Cholesterol Education Program

T

he relationship between the development and progression of ischemic heart disease and elevated levels of total and low-density lipoprotein (LDL) cholesterol has been established by various epidemiological studies.1 Similarly, the beneficial effects of LDL cholesterol lowering on cardiac events and mortality have been clearly demonstrated.2,3 Consequently, cholesterol lowering, as emphasized in the updated guidelines recently published by the National Cholesterol Education Program (NCEP), has become a major strategy for reducing the incidence and progression of ischemic heart disease.4 A combination of diet and drug therapy is prescribed to most patients with hypercholesterolemia. However, some patients, primarily those with familial hypercholesterolemia (FH), may require additional therapy. In recent years, LDL apheresis has emerged as an effective method of lipid lowering in these patients.5

result in defects of LDL receptor function, or its complete absence, in hepatocytes and peripheral tissues.6 The LDL receptor is essential for the receptor-mediated endocytosis of plasma LDL and its delivery to lysosomes, where cholesterol is released for metabolic use. When LDL receptors are deficient, the rate of removal of LDL cholesterol from plasma declines, and the level of LDL cholesterol rises in inverse proportion to the receptor number. Cholesterol concentrations are elevated 3- to 6-fold above normal concentrations in homozygous patients. Homozygous FH occurs with a frequency of 1 in 1 million persons in North America. However, FH is more common in certain populations such as French Canadians and people of Dutch extraction. In Lebanon, the estimated prevalence of homozygous FH is as high as 1 in 10,000 persons.7 These subjects come to clinical attention early in life because of premature ischemic heart disease, hypercholesterolemia, or both.6 In addition to the xanthelasma and tendon xanthomas found in heterozygous patients, homozygous individuals also develop planar xanthomas, which occur in the skin around areas of trauma. Homozygous patients are also susceptible to supravalvular aortic stenosis secondary to plaque formation in the aortic arch8 (Table 1). Marked development of atheroma in the proximal aorta is a feature unique to homozygous FH.9 In contrast, heterozygous FH is one of the more common single-gene disorders resulting in marked hypercholesterolemia, occurring with a frequency of 1 in 500 of the

FAMILIAL HYPERCHOLESTEROLEMIA Familial hypercholesterolemia is a relatively common disorder caused by mutations of the LDL receptor gene that From the Division of Endocrinology, Metabolism, Nutrition and Internal Medicine (A.V., T.O.) and Division of Transfusion Medicine (A.A.P.), Mayo Clinic, Rochester, Minn. Dr O’Brien is now with the Clinical Sciences Institute, University College Hospital, Galway, Ireland. Address reprint requests and correspondence to Timothy O’Brien, MD, PhD, Department of Medicine, Clinical Sciences Institute, University College Hospital, Galway, Ireland. Mayo Clin Proc. 2001;76:1039-1046

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Table 1. Characteristics of Homozygous and Heterozygous Familial Hypercholesterolemia* Clinical characteristic

Homozygous

Cholesterol (mg/dL) LDL cholesterol (mg/dL) Cutaneous features

≥600 ≥550 Xanthelasma Tendon xanthomas Tuberous xanthomas Planar xanthomas Possible before age 20 y Within 2nd decade

Corneal arcus Atherosclerosis

Heterozygous ≥300 ≥250 Tendon xanthomas Xanthelasma Common Within 4th-5th decade

*LDL = low-density lipoprotein.

general population. Affected subjects have 50% of the normal number of LDL receptors. Heterozygous patients typically have plasma cholesterol concentrations that are elevated 2- to 3-fold above average. As many as 25% of heterozygous FH patients do not have xanthomas. In populations in which particular LDL receptor mutations are frequent, these mutations can be detected directly with use of buffy-coat DNA and polymerase chain reaction–based techniques.6-10 However, in clinical practice, the diagnosis of FH is often made presumptively after documentation of an autosomal dominant pattern of inheritance of hypercholesterolemia in affected patients. Although the diagnosis of FH is fairly straightforward, satisfactory treatment with adequate lowering of total and LDL cholesterol is more difficult to achieve. THERAPY FOR HOMOZYGOUS FH Portocaval shunting has been advocated as therapy for FH. However, it is associated with high morbidity and mortality and is only partially effective.11 Partial ileal bypass is ineffective in homozygous FH patients.12 Another alternative is liver transplantation, but this has limited applicability and relatively high morbidity.13,14 The results of pilot studies of gene therapy involving hepatocyte-directed expression of the LDL receptor have been disappointing to date. Progress in vector technology is required before adequate gene transfection and stable receptor expression at therapeutic levels can be achieved.15 Low-density lipoprotein apheresis has rapidly been established as the treatment of choice for FH. Proof of the clinical utility of plasma exchange was first described by Thompson et al,16 who demonstrated the regression of xanthomas and delayed progression of atherosclerotic lesions with this modality. Plasma exchange was subsequently shown to improve survival of treated patients with homozygous FH compared with their untreated siblings with the same disorder.17 Moreover, several investigators18,19 using apheresis have documented mobilization of cholesterol from the tissues of affected patients.

Some homozygous patients may produce a defective LDL receptor and exhibit a partial response to 3-hydroxy3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. Low-density lipoprotein apheresis is still required in these patients if optimal lipid lowering is to be achieved.20 THERAPY FOR HETEROZYGOUS FH Although HMG-CoA reductase inhibitors have greatly facilitated management of heterozygous FH patients, many continue to require combination therapy with other classes of lipid-lowering drugs such as niacin and resins. Combination therapy, while well tolerated by the majority of patients, is associated with an increased incidence of myositis and hepatitis, which may lead to discontinuation of therapy. Currently, LDL apheresis is approved for use in homozygous FH patients with an LDL cholesterol level of 500 mg/dL or higher, heterozygous patients with an LDL cholesterol level of 300 mg/dL or higher, or heterozygous patients with documented ischemic heart disease and an LDL cholesterol level of 200 mg/dL or higher. In heterozygous patients, failure of maximum tolerated combination drug therapy and an adequate trial of drugs from at least 2 separate classes of lipid-lowering agents must be documented prior to initiating apheresis21 (Table 2). LDL APHERESIS SYSTEMS Plasmapheresis was the initial physical method used in clinical practice to lower cholesterol levels16,22 and has also been used successfully in young children.23 Plasmapheresis relies on membrane or centrifuge separation of plasma from whole blood. Albumin is then infused as a substitute solution for plasma. Although simple and efficient, plasmapheresis has 2 major disadvantages. The first is the lack of selectivity of the process; immunoglobulins as well as high-density lipoprotein (HDL) are removed together with LDL. Second, the cost of albumin required to replace plasma is substantial.

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Mayo Clin Proc, October 2001, Vol 76

Double-filtration plasmapheresis (DFPP) evolved from plasmapheresis by the addition of a secondary filter to the plasma circuit. The resultant filtrate is then reinfused. Although albumin is not required, the system is nonselective and eliminates HDL and immunoglobulins from the circulation.24,25 The thermofiltration system is similar to DFPP; the secondary filter in the plasma circuit is warmed to about 40ºC. Warming the secondary filter prevents the formation of a cryogel, which occurs when heparinized plasma is cooled below 35ºC. Cryogel formation (as occurs in DFPP) occludes the larger membrane pores of the secondary filter thereby decreasing the LDL-HDL selectivity of the filter. The dextran sulfate cellulose adsorption system uses columns containing dextran sulfate immobilized on cellulose beads to remove LDL from the plasma.25 Typically, there are 2 such columns in the plasma circuit, which are regenerated automatically during LDL apheresis.26 The system has a high selectivity for the removal of apolipoprotein B (apo B)–containing lipoproteins, removing LDL, very low-density lipoprotein, and lipoprotein(a). Binding of LDL appears to depend on electrostatic interaction between dextran sulfate and apo B and is inhibited by acetylation of LDL.27 Interestingly, dextran sulfate columns are able to remove LDL of patients with familial defective apo B-100 with equal efficacy.28 Although some molecules with similar properties are adsorbed to the column, this is not associated with any adverse clinical consequences. The columns are discarded after each apheresis procedure, and this contributes to the high running costs of this system. The LDL–ab-adsorber system is similar to the dextran sulfate adsorber. However, instead of dextran sulfate, anti– apo B-100 goat antibodies are immobilized on cellulose beads.24 This system is sometimes associated with the “first use” syndrome, an immune phenomenon mediated by heterophile antibodies the manifestations of which include pyrexia and hypotension. The heterophile antibodies are generated against the goat antibodies during circulation through the extracorporeal system.29 The heparin extracorporeal LDL precipitation (HELP) system involves the removal of LDL-heparin complexes generated by the addition of heparin to plasma and their selective precipitation at a pH of 5.2. It is a system that can effectively remove LDL and fibrinogen. However, this system requires a filter, dialyzer, heparin, and buffer solution as well as a skilled operator to run it effectively.30 The recently developed direct adsorption of lipoproteins system uses columns of polyacrylate-coated polyacrylamide to remove apo B–containing lipoproteins from whole blood.31 This removal of lipoproteins from whole blood is due to an electrochemical interaction between the cationic

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Table 2. Food and Drug Administration Criteria Required for Commencement of LDL Apheresis* Patient characteristic Homozygous FH Heterozygous FH and failure of medical therapy Heterozygous FH with documented coronary disease and failure of medical therapy

LDL cholesterol (mg/dL) ≥500 ≥300 ≥200

*FH = familial hypercholesterolemia; LDL = low-density lipoprotein.

groups of the lipoproteins with the column surface. Prolongation of the activated partial thromboplastin time has been noted after apheresis with this system. Because of this, less heparin is required to prevent extracorporeal clotting during apheresis in comparison with conventional systems.32 Because positively charged electrolytes bind to the adsorber surface, the columns must be flushed with a rinsing fluid containing these electrolytes to prevent derangement of electrolyte concentrations in the patient undergoing apheresis.33 CONTRAINDICATIONS AND ADVERSE REACTIONS Use of dextran sulfate columns or HELP for LDL apheresis, as is currently the clinical practice in North America, requires heparinization to prevent blood coagulation within the extracorporeal system. Patients receive a loading dose of 2000 IU of heparin followed by an intravenous infusion at a rate of 25 IU/kg per hour. Patients in whom heparin would cause uncontrolled anticoagulation or those in whom adequate anticoagulation cannot be achieved safely (eg, in the postoperative period) cannot undergo LDL apheresis, nor can patients with known hypersensitivity to heparin or ethylene oxide (present in the dextran sulfate columns). Bradykinin, which is generated in the extracorporeal circuit when blood comes into contact with a nonphysiologic surface, can cause hypotension. Although uncommon (1.3% of episodes of apheresis), systemic hypotension can have serious consequences in patients with widespread vascular disease. Angiotensin-converting enzyme inhibitors (ACEIs) interfere with the metabolism of bradykinin34-36; their use is associated with an increased incidence of hypotension during LDL apheresis, a relative contraindication to this procedure.37-39 However, recent experience has suggested that ACEI administration can be safe if use is discontinued 24 hours prior to apheresis.37,40 In refractory cases, bradykinin receptor inhibitors have been shown to prevent the hypotension associated with ACEI use.41 Angina and hemolysis are the other adverse effects associated with the dextran sulfate system. These occur in 0.1% of all apheresis procedures.42

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LDL Apheresis

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300

Cholesterol (mg/dL)

TC LDL

200

100

0

Before apheresis

After apheresis

Figure 1. Response to low-density lipoprotein (LDL) apheresis observed in 6 patients with familial hypercholesterolemia (heterozygous). Error bars indicate mean ± SEM. TC = total cholesterol.

THE RATIONALE FOR LIPOPROTEIN APHERESIS Lipoprotein apheresis is a treatment that is administered periodically, usually with 2-week intervals between treatments. Plasma levels of LDL between treatments determine the therapeutic benefit of the procedure and the frequency with which it is required.42,43 Large reductions (>100 mg/dL) are observed in both total and LDL cholesterol levels after an apheresis procedure (Figure 1). However, these levels increase gradually over a 14-day period after the initial procedure. The increase in cholesterol is less rapid during the second week after apheresis. In most patients, the peak total and LDL cholesterol levels seen 2 weeks after the initial apheresis are lower than the values prior to apheresis. Simultaneous therapy with an

Cholesterol (mg/dL)

400

Apheresis alone (n=6) Apheresis and lovastatin (n=6)

200

0

Before A apheresis

1

3

5

7

After apheresis (d)

Figure 2. Addition of a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor reduces the rate of increase of total cholesterol after apheresis (A). The total cholesterol rises to a lower level at 7 days after apheresis than was present before apheresis (adapted with permission from Pfohl et al45).

HMG-CoA reductase inhibitor reduces the rate of rise of total and LDL cholesterol levels after LDL apheresis, further increasing the discrepancy between the initial level of LDL cholesterol and that obtained prior to the next apheresis5,44,45 (Figure 2). In this way, regular LDL apheresis allows mean total and LDL cholesterol concentrations to be maintained at levels closer to those recommended by the NCEP guidelines for primary and secondary prevention (Figure 3). Low-density lipoprotein that undergoes oxidation or acetylation can be taken up by macrophage scavenger receptors and lead to the formation of foam cells in the arterial wall. Selective LDL apheresis has been shown to decrease LDL peroxidation and oxidation, in addition to decreasing total concentrations of LDL.46-48 Interestingly, some interindividual variability occurs in response to LDL apheresis. Some individuals maintain a 70% reduction in LDL cholesterol for more than 3 weeks after apheresis, while in others this reduction is maintained for no longer than 7 days after the procedure. The frequency of LDL apheresis has to be determined for each patient by careful follow-up of cholesterol levels after apheresis.42 IS THERE EVIDENCE TO SUPPORT THE USE OF LDL APHERESIS? Aggressive lowering of elevated total and LDL cholesterol forms the mainstay of primary and secondary prevention of ischemic heart disease. The rationale for this approach is provided by several studies that demonstrate that cholesterol lowering improves survival and outcomes in patients with ischemic heart disease.49 The ability of LDL apheresis to lower total and LDL cholesterol concentrations to levels associated with stabilization or regression of coronary artery disease is well documented.50 However, it is less clear whether LDL apheresis can actually improve outcomes in FH heterozygotes and FH homozygotes with hypercholesterolemia. The lack of clear outcomes data is attributable to the considerable logistical difficulties associated with conducting such studies with adequate statistical power. Furthermore, such studies cannot be blinded owing to the nature of the intervention. Although most of the available studies are uncontrolled and include small numbers of patients, the results are impressive when compared with the natural history of patients with severe, untreated hyperlipidemia. It must also be borne in mind that lack of progression as well as regression of symptoms and disease is a positive outcome of intervention in patients with FH. The HELP–LDL apheresis multicenter study51 was an uncontrolled 10-center study in which 51 FH patients were treated with weekly LDL apheresis. The patients were

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500

Cholesterol (mg/dL)

evaluated after 2 years of treatment for changes in symptoms and in coronary artery lesions. The number of patients without angina increased from 7 at commencement of the study to 15 at the end of the study. Computer-assisted analysis of paired angiograms revealed lesion regression in 23 of 33 evaluable patients. The most frequent adverse effect encountered was angina that occurred during 1.2% of all treatments.52 The LDL apheresis regression study,53 a 13-center uncontrolled trial in Japan, used dextran sulfate cellulose columns for LDL apheresis. Thirty-seven patients were studied (7 homozygous FH patients, 25 heterozygous FH patients, and 5 patients with common variable hyperlipidemia) and treated with LDL apheresis for at least 1 year at varying frequencies. Most patients received some form of additional drug therapy such as pravastatin or probucol. Angiography was performed at the start of the study and then after 1 year of treatment. Visual analysis of these paired angiograms revealed that 14 patients had regression of their ischemic heart disease, no change was observed in 18 patients, and the remaining 5 had progression. Interestingly, subset analysis confirmed that the presence of multiple nonlipid risk factors for coronary heart disease (such as smoking) prevented the regression of atherosclerosis in this study. The German multicenter LDL apheresis trial19 studied 32 patients with a total cholesterol level higher than 250 mg/dL despite drug therapy. Apheresis was performed weekly. Of the 25 patients who completed the study, all experienced symptomatic improvement in their angina. Achilles tendon thickness was decreased bilaterally, consistent with mobilization and resorption of cholesterol from the tissues. Comparison of angiograms obtained after 3 years of therapy with baseline studies did not reveal any regression of atheroma. However, progression was documented in only 5 patients. The FH regression study54 recruited heterozygous FH patients (total cholesterol >310 mg/dL) who were randomly allocated to receive biweekly apheresis and simvastatin or simvastatin and colestipol for 2 years. Angiography was performed on all subjects at baseline and after 2 years of therapy. Changes in serum lipoprotein levels were similar in both groups apart from a greater lowering of LDL cholesterol by apheresis. Serial exercise electrocardiographic findings improved in both groups compared with baseline. Although the primary angiographic end points were not significantly different between groups, changes in stenosis diameter in individual patients were comparable to those achieved in trials with conventional lipid lowering. This study has subsequently been criticized because it did not recruit patients who had failed maximal, optimal drug therapy. The patients receiving medication

LDL Apheresis

250

0 0

25

50

75

100

Days

Figure 3. The changes in serum total cholesterol concentrations observed in 6 patients in response to repeated biweekly apheresis (represented by arrowheads). Error bars indicate mean ± SEM.

alone were all able to achieve their target LDL. The results of this study imply that LDL apheresis should be reserved for those heterozygous FH patients who have failed drug therapy.55,56 The LDL apheresis atherosclerosis regression study57,58 was a randomized study that compared the effect of simvastatin and LDL apheresis with drug therapy alone in patients who had regional myocardial perfusion. Forty-two patients with severe hypercholesterolemia and coronary artery disease were randomly assigned to receive treatment with apheresis and simvastatin or simvastatin alone. Biweekly LDL apheresis and simvastatin decreased the LDL cholesterol level by an additional 31% compared with medication alone. The investigators were able to demonstrate an improvement in regional myocardial perfusion and exercise tolerance in the apheresis group compared with the group receiving medication alone.57,58 Over the 2year period, no differences in primary angiographic end points were observed between groups. However, the significant functional improvement seen in the apheresis group implies that functional improvement precedes angiographic changes. In a study59 of 43 heterozygous FH patients treated with cholesterol-lowering drugs combined with LDL apheresis and 87 heterozygous patients treated with medication alone, apheresis was associated with a 72% lower incidence of coronary events. The proportion of patients who did not require coronary artery bypass grafting or angioplasty was also significantly higher in the apheresis group. All patients enrolled in this study had coronary heart disease documented by angiography prior to entry into the study. The study also demonstrated the sustained benefit of LDL apheresis over a 6-year period. Patients with peripheral vascular disease have experienced symptomatic relief 60,61 together with improved circulation of blood to the skin and elevations in nitric oxide.62

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Similarly, cerebrovascular63 and skeletal muscle64 blood flow in hypercholesterolemic patients improves rapidly after LDL apheresis. Mellwig et al65 demonstrated a 30% improvement in coronary vasodilatation capacity secondary to improved endothelial function, as measured by positron emission tomography within 24 hours of LDL apheresis. These results mirror those achieved by Tamai et al66 who demonstrated augmented vasodilator responses to acetylcholine after a single session of LDL apheresis in hypercholesterolemic patients. The improvement in vasodilatory response to acetylcholine correlated with the degree of reduction in LDL cholesterol. OTHER USES OF LDL APHERESIS Low-density lipoprotein apheresis may have applications other than the treatment of refractory hypercholesterolemia. These include the prevention and treatment of restenosis after angioplasty. Three studies67-69 have suggested that apheresis performed in patients immediately before and after angioplasty was associated with a lower restenosis rate compared with control patients who did not undergo apheresis. Although these studies suffer from several methodological limitations, this intriguing observation merits prospective testing in a randomized controlled trial. Accelerated ischemic heart disease is commonly seen in cardiac transplant recipients. This is refractory to conventional treatment because of its accelerated course, multifocal nature, and the involvement of smaller vessels that are not amenable to bypass or angioplasty.70,71 In addition, the use of LDL apheresis in the treatment of transplant-associated ischemic heart disease72,73 has resulted in slower progression or regression of disease on serial angiography. The applicability of this intervention to transplant recipients with normal cholesterol concentrations is unknown. The pathogenic role of hyperlipidemia in long-standing nephrotic syndrome is known to be associated with the progression of glomerulosclerosis and tubulointerstitial injury in focal segmental glomerulosclerosis.74 Aggressive lipid-lowering treatment with LDL apheresis in patients with steroid-resistant nephrotic syndrome (focal segmental glomerulosclerosis or minimal change nephrotic syndrome) led to a rapid improvement of hyperlipidemia, a significant decrease of urinary protein, and an increase of serum albumin in some series.75,76 As yet, these observations have not been tested prospectively by a randomized controlled trial, but these and other reports of a beneficial effect of LDL apheresis in the nephrotic syndrome and other kidney disease77-79 are provocative and merit further investigation.

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CONCLUSIONS An elevated LDL cholesterol concentration can in many cases be treated by dietary and single-drug therapy. However, certain subsets of patients, most notably homozygous and heterozygous FH patients, require referral to a lipid specialty clinic for institution of multiple-drug regimens. Patients who are drug intolerant or in whom drugs fail to achieve appropriate reduction of LDL cholesterol may require additional therapy in the form of LDL apheresis. Current guidelines for initiation of LDL apheresis in heterozygous FH patients with ischemic heart disease require an LDL cholesterol level of 200 mg/dL or higher. Current guidelines for the secondary prevention of ischemic heart disease advocate reduction of the LDL cholesterol level to 100 mg/dL or lower. It may be reasonable to extend use of LDL apheresis to patients with persistent elevations of LDL cholesterol despite maximal tolerated dietary and drug therapy. Systems that use dextran sulfate columns or heparin precipitation of LDL cholesterol selectively and effectively remove LDL from the plasma. More importantly, HDL cholesterol is not reduced significantly as is observed in LDL apheresis that uses less selective systems. Selective LDL apheresis is of proven value in the treatment of these patients and has a low incidence of adverse events; thus, it can be performed safely and effectively on an outpatient basis. Unfortunately, at present LDL apheresis is available only in a limited number of tertiary referral centers, limiting its applicability to the general population. The cost of approximately $2000 per session, although comparing favorably to plasmapheresis (or interventional procedures for ischemic heart disease), is another important barrier to its use. These factors as well the psychological implications of lifelong biweekly therapy should be considered when recommending LDL apheresis to individual patients. REFERENCES 1.

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