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Low-Density Lipoprotein Apheresis as a Treatment Option for Hyperlipidemia
Puja K. Mehta, MD, Jefferson Baer, MD, MPH, Christine Nell, NP-C, MPH, MSN, and Laurence S. Sperling, MD
Current Treatment Options in Cardiovascular Medicine 2009, 11:279-288
Current Medicine Group LLC ISSN 1092-8464
Copyright © 2010 by Current Medicine Group LLC
Opinion Statement
Data support the relevance of blood cholesterol levels, particularly high levels of low-density lipoprotein (LDL), in the pathogenesis and progression of atherosclerosis. A strong and continuous relationship between dyslipidemia and vascular morbidity and mortality has been established. The initial approach to treating dyslipidemia consists of lifestyle modifications followed by pharmacologic therapy, usually beginning with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Some patients with familial hypercholesterolemia (FH) fail to achieve their LDL goal despite aggressive pharmacologic therapy. In certain cases, LDL apheresis may be an effective therapeutic option. In the United States, LDL apheresis is approved for homozygous FH patients with an LDL cholesterol level ≥ 500 mg/dL. For patients with heterozygous FH, LDL apheresis may be offered if their LDL is ≥ 300 mg/dL, or ≥ 200 mg/dL with known coronary artery disease, despite maximum medical treatment. This review focuses on the principles and methods of LDL apheresis, its potential benefit in clinical care, and its current indications.
Introduction
CASE VIGNETTE
A 25-year-old woman with familial hypercholesterolemia (FH) and a history of coronary artery bypass grafting was referred to our preventive cardiology center for low-density lipoprotein (LDL) apheresis. She had a family history of coronary artery disease (CAD)-related deaths in several members during their second or third decade of life. She was unable to lower her cholesterol levels despite a low-fat diet and four cholesterol-lowering medications; her LDL remained well above 200 mg/dL. On physical examination, she had prominent bilateral corneal arcus; xanthelasma on her eyelids, knees, and some of her knuckles; and xanthomas on her Achilles tendons. Auscultation revealed bruits over her carotid, abdominal, and femoral arteries. She had a grade III/VI systolic murmur heard loudest at the base. She was an appropriate candidate for LDL apheresis and began receiving biweekly treatments.
Now, 5 years later, she is doing well. To prepare for each treatment, she drinks plenty of fluids 48 hours before the procedure. She withholds her antihypertensive medication 24 hours before apheresis, but takes an aspirin to prevent clot formation in the machine tubing. She applies a topical lidocaine cream to the antecubital fossa before arrival to lessen the pain from the needles. On arrival, nurses perform a baseline assessment, check vital signs, take blood samples, and obtain intravenous access in both arms, which connects her to the machine. By the end of her 2.5-hour apheresis session, approximately 3000 mL of plasma has circulated in the machine and is returned to her. At the end of her session, she has a dramatic reduction in atherogenic particles (Fig. 1). Before leaving, she is given fluids and healthy snacks. After her apheresis treatment, she is able to drive home and resume her usual daily activities.
Figure 1
The effect of low-density lipoprotein (LDL) apheresis on total cholesterol (TC), LDL, high-density lipoprotein (HDL), triglycerides (TG), and lipoprotein (a) [Lp(a)] in the patient presented in the case vignette.
View larger image
DISCUSSION
Data have solidified the role of LDL cholesterol in the pathogenesis and progression of atherosclerotic cardiovascular disease. Additionally, LDL lowering has a powerful effect on cardiovascular morbidity and mortality [1, 2, 3, 4]. Targeting LDL levels via therapeutic lifestyle changes and pharmacologic manipulation remains the mainstay of treatment for the primary and secondary prevention of cardiovascular disease. However, in a small subset of FH patients, these therapeutic options have limited benefit in lowering LDL cholesterol. For these patients, plasma LDL apheresis is an effective option.
Patients with FH, an inherited disorder involving mutations in the LDL receptor (LDL-R), may benefit from LDL apheresis [5]. In FH, a defect in the LDL-R gene results in absence or impaired function of the LDL-R in hepatic and peripheral tissues, resulting in impaired hepatic clearance of LDL cholesterol. Patients with a mutation in one (heterozygous) or both (homozygous) genes have markedly elevated LDL cholesterol and are at increased risk for premature CAD compared with the general population. Homozygous FH occurs in 1 in 1 million people in North America. Importantly, it is most common in Lebanon, with a prevalence of 1 in 10,000 [6]. Other populations with increased prevalence are French Canadians and South Africans. Heterozygous FH is much more common, occurring with a frequency of 1 in 500 in the general population, and is the most common monogenetic disorder in North America and Europe [7]. Patients with heterozygous FH often manifest CAD in early to mid-adulthood [7]. Heterozygous and homozygous FH patients may have tendon xanthomas, xanthelasma, and corneal arcus. Homozygous patients also may have planar and tuberous xanthomas. Interestingly, FH was the first genetic disorder recognized to cause myocardial infarction. Patients with homozygous FH frequently have rapidly progressive coronary atherosclerosis with angina pectoris, myocardial infarction, or sudden death at a young age, typically manifesting CAD by the first two decades of life [7].
Although lifestyle changes and pharmacologic treatment remain important adjunctive therapies in patients with severe hypercholesterolemia, LDL apheresis may provide a beneficial primary mode of treatment. LDL apheresis refers to the extracorporeal removal of circulating LDL cholesterol by plasma exchange or by more selective methods. Although the term LDL apheresis implies LDL cholesterol removal, lipoprotein (a) [Lp(a)], triglycerides, high-density lipoprotein (HDL), and fibrinogen also are removed to various degrees (Table 1). This review focuses on the principles and methods of LDL apheresis, trials suggesting its benefit, current indications for apheresis, and its advantages and disadvantages.
Table 1:  Comparison of HELP* and Liposorber LA-15† LDL apheresis methods
Parameter HELP Liposorber LA-15
LDL reduction rate, %
 LDL 500 mg/dL, 60 kg 60 73-83
 LDL 500 mg/dL, 90 kg 60 73-83
 LDL 250 mg/dL, 60 kg 60-64 73-83
 LDL 250 mg/dL, 90 kg 60-64 73-83
Plasma volume treated, mL ≈ 3000 ≈ 9990
Extracorporeal volume, mL 590 420
Minimum body weight, kg 37 15
ACE-I contraindicated? No Yes (ARBs OK)
Treatment time, h 2-3 (depends on plasma volume treated) 2-3 (depends on plasma volume treated)
*Trademark of B. Braun, Melsungen, Germany.
†Trademark of Kaneka Corp., Osaka, Japan.
ACE-I--angiotensin-converting enzyme inhibitor; ARBs--angiotensin receptor blockers; HELP--heparin-mediated extracorporeal precipitation; LDL--low-density lipoprotein.
(Data from the US Food and Drug Administration [47, 48].)
LDL apheresis
Methods 
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In LDL apheresis, venous blood passes through a column that separates plasma from other blood components via membranes or centrifugation, and LDL cholesterol is removed. Several techniques are used, including immunoadsorption (IA), plasmapheresis, dextran sulfate adsorption (DSA), and heparin-mediated extracorporeal precipitation (HELP; B. Braun, Melsungen, Germany). Regardless of the method used to initiate LDL apheresis, temporary venous access must be established. More than 50% of patients can be treated via the antecubital vein, accessed from both arms with the patient seated and the arms extended. Blood is removed from one arm, pumped through the apheresis circuit, and returned to the other arm. Less than 1 pint of blood circulates outside the body. If the antecubital vein is not large enough or is inaccessible, then a central venous catheter may be used. Rarely, an arteriovenous fistula or graft may be required. In our center, all but one of our patients can use peripheral venous access.
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A typical apheresis session lasts about 3 hours; sessions usually are performed every 2 weeks for patients with heterozygous FH and every 7 to 10 days for those with homozygous FH. The need for and frequency of LDL apheresis depend on the degree of hyperlipidemia and response to treatment. Of the following five apheresis methods, only DSA and HELP are approved by the US Food and Drug Administration (FDA).
Immunoadsorption
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In IA apheresis, plasma is separated from the patient's blood by a continuous cell separator. Plasma is then pumped through a series of columns containing polyclonal sheep antibodies against apolipoprotein B100 (apo B)-containing lipoproteins, coupled to Sepharose gel matrix (Amersham, Louisville, CO) [8]. Thus, apo B-containing lipoproteins, including LDL, very low-density lipoprotein (VLDL), and Lp(a), are removed. Anticoagulation is needed and maintained by heparin and acid citrate dextrose; up to 6 L of plasma can be treated over a period of 3 to 4 hours [9].
Plasmapheresis
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In the late 1970s, plasmapheresis became the first clinical method to lower cholesterol levels [10, 11]. In this technique, plasma is separated from blood via membranes or centrifugation, and LDL cholesterol is removed. Anticoagulation is not required because plasma is not returned to the patient; it is replaced by albumin infusions, which are quite expensive. Furthermore, plasmapheresis is a nonspecific method of removing LDL cholesterol; important coagulation factors, immunoglobulins, and HDL particles also are removed, making it a less-than-ideal process. In a newer technique, plasma can be returned to the patient via a process called double-filtration plasmapheresis (DFPP). The DFPP technique requires systemic anticoagulation but does not require albumin infusions; however, it is still a nonselective process, and the problem of removing HDL and immunoglobulins remains [12*].
Direct adsorption of lipoprotein
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In 1993, Bosch et al. [13] introduced a method of direct adsorption of lipoproteins (DALI) from whole blood. The polyacrylamide beads in the adsorber column have a small pore size, which enables LDL cholesterol removal without the initial step of separating plasma from whole blood. The small pores prevent the larger red cells and platelets from being adsorbed. The column has to be primed with a buffer of heparin, calcium, and citrate to maintain a physiologic pH of 7.4 and to prevent clotting. Lp(a) also is removed, as are triglycerides and fibrinogen to a lesser extent. Various sizes of LDL adsorbers are available, depending on the patient and the severity of the LDL cholesterol level, ranging from the smaller capacity DALI-500 (480 mL) to the larger DALI-750 and DALI-1000 adsorbers for homozygous FH patients [9].
Dextran sulfate adsorption
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In the FDA-approved DSA method of LDL apheresis, plasma is separated from blood and passed over two cellulose-bead columns containing dextran sulfate. Via electrostatic binding, dextran sulfate removes apo B-containing particles. This safe method has the advantage of not removing particles such as HDL or albumin [14, 15]. Via the Liposorber system (Kaneka Corp., Osaka, Japan), once plasma is cleared of LDL particles, it is combined with the patient's blood cells and whole blood is returned to the patient. Heparin is required for anticoagulation in this process to prevent extracorporeal blood clotting; therefore, if there is any contraindication to heparin use, neither DFPP nor DSA can be used. Usually a heparin dose of at least 25 U/kg is used as a loading dose, with a maintenance dosage of 25 U/kg per hour to provide adequate anticoagulation. In addition, patients allergic to ethylene oxide cannot be treated with DSA because of the presence of ethylene glycol in the sulfate columns [6]. Because IA and DSA columns remove all apo B-containing lipoproteins, they have a theoretic advantage over hydroxymethylglutaryl coenzyme A inhibitors in that they decrease Lp(a) as well as LDL [16]. One of DSA's advantages over HELP is that it can process a greater volume of plasma and therefore achieve a greater percent reduction of LDL cholesterol (Table 2). Currently there are more than 60 Liposorber machines in use in the United States.
Table 2:  Approximate reductions in LDL, HDL, triglycerides, and Lp(a) with various apheresis techniques
Technique LDL, % HDL, % Triglycerides, % Lp(a), %
Plasmapheresis/DFFP 50-60 50-60 50 40
DSA 60 15 20-40 15
HELP 60-64 15 50 40
DFFP--double-filtration plasmapheresis; DSA--dextran sulfate adsorption; HDL--high-density lipoprotein; HELP--heparin-mediated extracorporeal precipitation; LDL--low-density lipoprotein; Lp(a)--lipoprotein (a).
Heparin extracorporeal LDL apheresis
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In HELP apheresis, LDL is precipitated and filtered from plasma by exploiting electrostatic properties. Plasma is separated from whole blood, passed through a heparin buffer, and acidified to a pH of 5.2. At this low pH, heparin becomes negatively charged and LDL positively charged, which enables the formation of heparin-LDL complexes. These complexes precipitate and are removed by filtration. Usually, 60% to 64% of LDL cholesterol, 65% to 75% of VLDL cholesterol, and 60% to 70% of Lp(a) is removed [16, 17]. Although HDL cholesterol levels acutely decrease immediately after LDL apheresis, this effect is transient. It has been shown that after several months of treatment with HELP apheresis, HDL cholesterol levels increase approximately 10% to 15% over baseline [18].
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Residual heparin is removed from the LDL-free plasma by a heparin adsorber, and plasma is returned to the patient. Like DSA columns and DFPP, HELP requires the use of heparin to prevent blood clots in the extracorporeal system; however, most of the heparin is removed before returning the plasma to the patient; thus, the advantage is that the patient is never fully anticoagulated. Like DSA, HELP apheresis is approved by the FDA for removal of apo B-containing atherogenic particles [17].
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HELP has potential advantages over DSA in that it is more effective in lowering fibrinogen and does not prohibit the use of angiotensin-converting enzyme inhibitors. Because less plasma is processed, the treatment session may be shorter; however, the LDL reduction also is less. There are approximately 10 HELP apheresis sites in the United States.
Benefits 
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Given the rarity of FH, there have been no large randomized controlled trials demonstrating the benefit of LDL apheresis on cardiovascular morbidity or mortality. However, in one of the largest observational studies on LDL apheresis, Mabuchi et al. [19] found that in 130 heterozygous FH patients with known angiographic CAD, the rate of total coronary events was 72% lower in the apheresis group compared with the group treated with medications (10% vs 36%, P = 0.0088). In addition, there have been numerous small studies (highlighted in this section) showing an angiographic benefit of LDL apheresis on coronary and peripheral arterial disease as well as on endothelial function, inflammatory markers, and coagulation. It should be noted that patients with FH are at high risk for a coronary event, so although most of the studies with LDL apheresis are uncontrolled, lack of disease progression indicates a significant benefit [6].
Observational studies and trials
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Several studies of LDL apheresis have suggested a significant benefit [17]. A study of 33 patients with known CAD demonstrated a reduction of mean coronary stenosis on quantitative coronary angiography from 32.5% to 30.6% over a 2-year period with drug therapy and HELP LDL apheresis [20]. In this study, a regression of greater than 8% was observed in 26.7% of segments; 57.8% of segments were stable and 15.5% progressed. The authors concluded that HELP LDL apheresis can stabilize atherosclerotic plaques and induces twice as much regression as progression. In a prospective nonrandomized trial by Waidner et al. [21], 25 patients with hypercholesterolemia refractory to medical therapy underwent weekly LDL apheresis for 3 years. At the end of the study period, mean LDL cholesterol levels decreased by 58%, and quantitative measurement of 111 circumscribed coronary stenoses revealed a mean stenosis degree of 45% ± 26% at entry and 43% ± 22% at final assessment, consistent with no significant change. A longer-term study examining the effect of 8.6 years of LDL apheresis on the cholesterol levels and coronary angiograms of heterozygous FH patients with known coronary atherosclerosis found a regression of coronary lesions in 4 of 34 patients and no progression in 29 patients [22]. The benefit of LDL apheresis also has been examined in patients with transplant vasculopathy; in eight patients with transplant CAD, the minimal luminal diameter (MLD) increased by 3.4 ± 1.15 mm (P < 0.0001) with HELP apheresis over a period of 1 to 2.5 years [23]. Another recent observational study of LDL apheresis in eight patients showed that coronary calcium score decreased with treatment, as shown on electron beam CT [24].
Randomized clinical trials
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The Familial Hypercholesterolemia Regression Study randomly assigned 39 heterozygous FH patients with CAD to biweekly LDL apheresis plus simvastatin (40 mg/d) or to the same dosage of simvastatin plus colestipol (20 g/d) [25]. After 2 years, LDL apheresis was associated with significantly greater reductions in LDL cholesterol and Lp(a). The LDL-Apheresis Atherosclerosis Regression Study (LAARS) randomly assigned 42 patients with severe primary hypercholesterolemia and coronary atherosclerosis to biweekly LDL apheresis plus simvastatin (40 mg/d) or to simvastatin alone. At 2 years, the mean reduction in LDL cholesterol was 63% and 47%, respectively [26]. Interestingly, on bicycle exercise testing, time to ST depressions and the level of maximal ST depression decreased significantly in the apheresis group compared with the medically managed group. Neither study showed a difference in coronary atherosclerosis as assessed by angiography.
•
In the Japan Low-Density Lipoprotein Apheresis Coronary Atherosclerosis Prospective Study (L-CAPS), Nishimura et al. [27] noted that of 36 patients with heterozygous FH and advanced CAD, the 25 patients in the group receiving LDL apheresis plus drug therapy showed angiographic regression of disease with an increase in MLD of 0.19 mm at a mean 2.3 years of follow-up. In comparison, in the group treated with drug therapy alone (n = 11), there was disease progression and the MLD decreased by 0.44 mm. In patients randomly assigned to drug therapy alone, the average LDL cholesterol level was 170 mg/dL, compared with the group receiving LDL apheresis plus drug therapy, which had a mean level of 140 mg/dL (P < 0.05).
•
The Low-Density Lipoprotein Apheresis Coronary Morphology and Reserve Trial (LACMART) [28] randomly assigned 18 FH patients to receive drug therapy alone or in addition to LDL apheresis. Using intravascular ultrasound during angiography, the investigators demonstrated that at 1 year, there was a decrease in plaque area of 0.69 mm2 and an increase in MLD of 0.12 mm in the LDL apheresis group. In the drug therapy group, not only were cholesterol levels not significantly lowered, but there was progression of disease, with an increase in plaque area of 0.017 mm2 and a decrease in MLD of 0.08 mm.
Carotid and peripheral arterial disease
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Several researchers have explored the potential role of LDL apheresis in treating carotid and peripheral arterial disease. In a study of seven patients with heterozygous FH, HELP apheresis reduced total and LDL cholesterol and fibrinogen levels, and led to a significant reduction in carotid plaque volume [29]. An additional study suggesting a benefit from LDL apheresis demonstrated carotid plaque regression compared with the control group in two patients with homozygous FH and nine with heterozygous FH [30]. The benefit of LDL apheresis also was demonstrated in a study of peripheral arterial disease examining the effects of LDL apheresis on aortotibial stenosis and carotid intima-media thickness. In a single-center, randomized study of 42 men with FH and known CAD [31], the number of hemodynamically significant stenoses of the aortotibial tract decreased from nine to seven in the group receiving LDL apheresis plus simvastatin, compared with an increase from six to 13 in the simvastatin-alone group (P = 0.002). In addition, the carotid intima-media thickness decreased by a mean of 0.05 ± 0.34 mm in the apheresis group and increased by 0.06 ± 0.38 mm in the simvastatin-only group (P < 0.001).
Inflammatory markers
•
During the past decade, it has become increasingly clear that inflammation plays a significant role in the initiation and progression of atherosclerosis. Several inflammatory markers, including C-reactive protein (CRP) [32], interleukin-6 [33], and serum amyloid A [34], predict increased events in patients with cardiovascular diseases. In patients with angina, levels of factors such as fibrinogen and von Willebrand factor antigen also have been associated with an increased risk of coronary events [35]. The anti-inflammatory effects of LDL apheresis and its effects on endothelial function are not fully known. Several studies suggest that LDL apheresis may provide both angiographic and physiologic improvement in the vascular wall.
•
A study using HELP apheresis in 22 patients with coronary heart disease demonstrated that a single treatment significantly decreased the circulating levels of high-sensitivity CRP, soluble vascular adhesion molecule 1, soluble E-selectin, lipopolysaccharide binding protein, endothelin 1, and monocyte chemoattractant protein 1 (MCP-1), on average, by 67%, 37%, 24%, 27%, 24%, and 15%, respectively [36]. LDL apheresis also reduced plasma matrix metalloproteinase 9 and serum tissue inhibitor of matrix metalloproteinase 1 levels in type 2 diabetic hemodialysis-dependent patients with arteriosclerosis obliterans [37]. In seven patients with severe hypercholesterolemia, CRP levels were markedly decreased after DSA apheresis [38]. In another study of 28 patients with peripheral arterial occlusive disease, LDL apheresis was performed 10 times for 5 weeks. Along with clinical improvement noted by a doubling of walking distance and decreased foot chillness or numbness, serum levels of high-sensitivity CRP and MCP-1 and plasma levels of fibrinogen statistically decreased after a single session of LDL apheresis [39].
•
Moriarty and Gibson [40] noted a potentially beneficial effect of LDL apheresis on lipoprotein-associated phospholipase A2 (PLA2), a proinflammatory participant in atherosclerosis and biomarker for coronary heart disease in eight patients. Patients with cardiovascular disease received five LDL apheresis treatments over a 3-month period. The mean direct LDL cholesterol level reduction was 60% (from 252 to 100 mg/dL). LDL apheresis was found to acutely reduce Lp-PLA2 by 21.4%. Over the course of treatment, Lp-PLA2 levels were reduced by 29%. Suppression of oxidative stress and improvement of endothelial function may occur with LDL apheresis; however, more research is needed to determine the effect of LDL apheresis on markers of inflammation in larger groups of patients.
Endothelial function and myocardial blood flow
•
Studies have shown that lowering cholesterol over the long term improves vascular endothelial function, but interestingly, even short-term removal of cholesterol by a single LDL apheresis treatment improves endothelium-dependent vasodilation in patients with hypercholesterolemia [41]. Chronic LDL apheresis also has been shown to improve brachial artery vasoactivity by ultrasound measurement of arterial flow velocity and end-diastolic diameter in patients with hypercholesterolemia [42].
•
One small study involving eight homozygous patients with FH suggested that apheresis also induces changes that render LDL less susceptible to oxidation [43]. Another study reported decreased oxidized LDL and improvement in endothelium-dependent vasodilatory responses to acetylcholine with a single LDL apheresis treatment [41].
•
LDL apheresis may improve myocardial blood flow as measured by positron emission tomography. In nine patients with documented CAD, Mellwig et al. [44] demonstrated a reduction in LDL cholesterol levels after apheresis (from 194 to 81 mg/dL), but myocardial blood flow also improved by 30% (173 vs 226 mL/min per 100 g) after dipyridamole stress. In addition, coronary flow reserve improved, minimum coronary resistance decreased, and plasma viscosity decreased. Combined evidence thus far indicates that endothelial function and myocardial blood flow improve after cholesterol levels decrease, even after a single session of LDL apheresis, implying a potential cardiovascular benefit beyond plaque regression.
Coagulation pathway
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LDL apheresis may cause an acute reduction in clotting factors such as factors V, VIII, XI, and XII. Platelets decrease by approximately 10% to 20% with IA and HELP apheresis but are unaffected by other methods. HELP apheresis has been shown to acutely reduce plasma viscosity and erythrocyte aggregation and to increase erythrocyte deformability.
Current indications 
•
In the United States, LDL apheresis is an approved treatment option for patients with homozygous FH who have an LDL cholesterol level ≥ 500 mg/dL. For patients with heterozygous FH, LDL apheresis may be offered if the LDL cholesterol is ≥ 300 mg/dL or if LDL cholesterol is ≥ 200 mg/dL with known ischemic coronary heart disease. Heterozygotes with LDL greater than 200 mg/dL must have documented CAD as evidenced by angiography, myocardial infarction, or progressive angina documented by history and stress testing. Exceptions to these guidelines have been made in certain patients based on medical necessity. A few case reports have shown that LDL apheresis in pregnant patients with FH is feasible and safe with adequate monitoring [45, 46]. These guidelines are not strongly clinically data driven, but rather based on economic and clinical utilization issues. Pharmacologic therapy with at least two separate classes of lipid-lowering medications and dietary therapy should be used for at least 6 months. Baseline LDL cholesterol level should be evaluated after a 6-month trial of a Step II American Heart Association diet. In the United Kingdom, LDL apheresis is also recommended for patients with aggressive CAD who have an Lp(a) level ≥ 60 mg/L and whose LDL cholesterol level remains greater than 3.2 mmol/L (123.7 mg/dL) despite medication. Interestingly, in Japan, LDL apheresis also has been used to treat peripheral vascular disease and nephrotic syndrome caused by focal glomerular sclerosis.
Potential limitations 
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LDL apheresis is usually safe and well tolerated. As with dialysis, patients may experience fatigue after a treatment cycle. Although the procedure may require up to 4 hours of treatment time, there are relatively few side effects. Hypotension has been noted in approximately 3% of patients [17]. Patients are usually asked to refrain from taking antihypertensive medication the day of their apheresis treatment. Specifically, angiotensin-converting enzyme inhibitors often are held for patients using the DSA delivery of LDL apheresis because of hypotension that may occur as a result of increased bradykinin levels during the procedure. The delivery of apheresis treatments is limited by their expense (at least $2000-$2500 per treatment session) and availability.
Disclosure
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No potential conflicts of interest relevant to this article were reported.
References and Recommended Reading
Recently published papers of particular interest have been highlighted as:
* Of importance
** Of major importance
1.
 Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994, 344:1383-1389.
2.
 Heart Protection Study Collaborative Group: MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002, 360:7-22.
>  View the PubMed notation for this reference.
3.
 LaRosa JC: Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. JAMA 1999, 282:2340-2346.
>  View the PubMed notation for this reference.
4.
 Shepherd J: Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995, 333:1301-1307.
>  View the PubMed notation for this reference.
5.
 Gordon BR: Advances in LDL-apheresis for the treatment of severe hypercholesterolemia. Curr Opin Lipidol 1994, 5:69-73.
>  View the PubMed notation for this reference.
6.
 Vella A: Low density lipoprotein apheresis for the treatment of refractory hypercholesterolemia. Mayo Clin Proc 2001, 76:1039-1046.
>  View the PubMed notation for this reference.
7.
 Kavey RE: Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the American Heart Association Expert Panel on Population and Prevention Science; the Councils on Cardiovascular Disease in the Young, Epidemiology and Prevention, Nutrition, Physical Activity and Metabolism, High Blood Pressure Research, Cardiovascular Nursing, and the Kidney in Heart Disease; and the Interdisciplinary Working Group on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation 2006, 114:2710-2738.
>  View the PubMed notation for this reference.
8.
 Richter WO: Three-year treatment of familial heterozygous hypercholesterolemia by extracorporeal low-density lipoprotein immunoadsorption with polyclonal apolipoprotein B antibodies. Metabolism 1993, 42:888-894.
>  View the PubMed notation for this reference.
9.
 Thompson GR: Recommendation for the use of LDL apheresis. Atherosclerosis 2008, 198:247-255.
>  View the PubMed notation for this reference.
10.
 Apstein CS: Effect of intensive plasmapheresis on the plasma cholesterol concentration with familial hypercholesterolemia. Atherosclerosis 1978, 31:105-115.
>  View the PubMed notation for this reference.
11.
 Thompson GR: Plasma exchange in the management of homozygous familial hypercholesterolaemia. Lancet 1975, 1:1208-1211.
>  View the PubMed notation for this reference.
12.
*		 Thompsen J: A systemic review of LDL apheresis in the treatment of cardiovascular disease. Atherosclerosis 2006, 189:31-38.
This comprehensive article reviews methods of LDL apheresis and its use in cardiovascular disease.
>  View the PubMed notation for this reference.
13.
 Bosch T: Lipid apheresis by hemoperfusion: in vitro efficacy and ex vivo biocompatibility of a new low-density lipoprotein adsorber compatible with human whole blood. Artif Organs 1993, 17:640-652.
>  View the PubMed notation for this reference.
14.
 Koga N: Efficacy and safety measures for low density lipoprotein apheresis treatment using dextran sulfate cellulose columns. Ther Apher 1999, 3:155-160.
>  View the PubMed notation for this reference.
15.
 Yokoyama S: Selective removal of low density lipoprotein by plasmapheresis in familial hypercholesterolemia. Arteriosclerosis 1985, 5:613-622.
>  View the PubMed notation for this reference.
16.
 Gordon BR: Indications for low-density lipoprotein apheresis. Am J Cardiol 1994, 74:1109-1112.
>  View the PubMed notation for this reference.
17.
 Ziajka P: Role of low-density lipoprotein apheresis. Am J Cardiol 2005, 96:67E-69E.
>  View the PubMed notation for this reference.
18.
 Seidel D: The HELP-LDL-apheresis multicentre study, an angiographically assessed trial on the role of LDL-apheresis in the secondary prevention of coronary heart disease I. HELP Study Group. Eur J Clin Invest 1991, 21:375-383.
>  View the PubMed notation for this reference.
19.
 Mabuchi H: Long term efficacy of low-density lipoprotein apheresis on coronary heart disease in familial hypercholesterolemia. Hokuriku-FH-LDL-Apheresis Study Group. Am J Cardiol 1998, 82:1489-1495.
>  View the PubMed notation for this reference.
20.
 Schuff-Werner P: The HELP-LDL-apheresis multicentre study, and angiographically assessed trial on the role of LDL-apheresis in the secondary prevention of coronary heart disease II. HELP Study Group. Eur J Clin Invest 1994, 24:724-732.
>  View the PubMed notation for this reference.
21.
 Waidner T: The effect of LDL apheresis on progression of coronary artery disease in patients with familial hypercholesterolemia. Results of a multicenter LDL apheresis study. Clin Investig 1994, 72:858-863.
>  View the PubMed notation for this reference.
22.
 Richter WO: Long-term effect of low-density lipoprotein apheresis on plasma lipoproteins and coronary heart disease in native vessels and coronary bypass in severe heterozygous familial hypercholesterolemia. Metabolism 1998, 47:863-868.
>  View the PubMed notation for this reference.
23.
 Park JW: Regression of transplant coronary artery disease during chronic low-density lipoprotein-apheresis. J Heart Lung Transplant 1997, 16:290-297.
>  View the PubMed notation for this reference.
24.
 Hoffmann U: Effects of combined low-density lipoprotein apheresis and aggressive statin therapy on coronary calcified plaque as measured by computed tomography. Am J Cardiol 2003, 91:461-464.
>  View the PubMed notation for this reference.
25.
 Thompson GR: Familial Hypercholesterolemia Regression Study: a randomized trial of low-density-lipoprotein apheresis. Lancet 1995, 345:811-816.
>  View the PubMed notation for this reference.
26.
 Kroon AA: LDL-Apheresis Atherosclerosis Regression Study (LAARS). Effect of aggressive versus conventional lipid lowering treatment on coronary atherosclerosis. Circulation 1996, 93:1826-1835.
>  View the PubMed notation for this reference.
27.
 Nishimura S: Effects of intensive lipid lowering by low-density lipoprotein apheresis on regression of coronary atherosclerosis in patients with familial hypercholesterolemia: Japan Low-density Lipoprotein Apheresis Coronary Atherosclerosis Prospective Study (L-CAPS). Atherosclerosis 1999, 144:409-417.
>  View the PubMed notation for this reference.
28.
 Matsuzaki M: Intravascular ultrasound evaluation of coronary plaque regression by low density lipoprotein-apheresis in familial hypercholesterolemia: the Low Density Lipoprotein-Apheresis Coronary Morphology and Reserve Trial (LACMART). J Am Coll Cardiol 2002, 40:220-227.
>  View the PubMed notation for this reference.
29.
 Hennerici M: Regression of carotid plaques during low density lipoprotein cholesterol elimination. Stroke 1991, 22:989-992.
>  View the PubMed notation for this reference.
30.
 Koga N: Long-term effects of LDL apheresis on carotid arterial atherosclerosis in familial hypercholesterolaemic patients. J Intern Med 1999, 246:35-43.
>  View the PubMed notation for this reference.
31.
 Kroon AA: Effect of apheresis of low-density lipoprotein on peripheral vascular disease in hypercholesterolemic patients with coronary artery disease. Ann Intern Med 1996, 125:945-954.
>  View the PubMed notation for this reference.
32.
 Kinlay S: Inflammatory biomarkers in stable atherosclerosis. Am J Cardiol 2006, 98:2P-8P.
>  View the PubMed notation for this reference.
33.
 Kuo LT: Serum interleukin-6 levels, not genotype, correlate with coronary plaque complexity. Int Heart J 2008, 49:391-402.
>  View the PubMed notation for this reference.
34.
 Wang X: Serum amyloid A induces endothelial dysfunction in porcine coronary arteries and human coronary artery endothelial cells. Am J Physiol Heart Circ Physiol 2008, 295:H2399-H2408.
>  View the PubMed notation for this reference.
35.
 Thompson SG: Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. N Engl J Med 1995, 332:635-641.
>  View the PubMed notation for this reference.
36.
 Wang Y: Effects of heparin-mediated extracorporeal low-density lipoprotein precipitation beyond lowering proatherogenic lipoproteins--reduction of circulating proinflammatory and procoagulatory markers. Atherosclerosis 2004, 175:145-150.
>  View the PubMed notation for this reference.
37.
 Nakamura T: Effects of low-density lipoprotein apheresis on plasma matrix metalloproteinase-9 and serum tissue inhibitor of metalloproteinase-1 levels in diabetic hemodialysis patients with arteriosclerosis obliterans. ASAIO J 2003, 49:430-434.
>  View the PubMed notation for this reference.
38.
 Kojima S: Changes in C-reactive protein plasma levels during low-density lipoprotein apheresis. Ther Apher Dial 2003, 7:431-434.
>  View the PubMed notation for this reference.
39.
 Kobayashi S: LDL-apheresis improves peripheral arterial occlusive disease with an implication for anti-inflammatory effects. J Clin Apher 2005, 20:239-243.
>  View the PubMed notation for this reference.
40.
 Moriarty PM: Effects of low-density lipoprotein apheresis on lipoprotein-associated phospholipase A2. Am J Cardiol 2005, 95:1246-1247.
>  View the PubMed notation for this reference.
41.
 Tamai O: Single LDL apheresis improves endothelium-dependent vasodilation in hypercholesterolemic humans. Circulation 1997, 95:76-82.
>  View the PubMed notation for this reference.
42.
 Stadler RW: Peripheral vasoactivity in familial hypercholesterolemic subjects treated with heparin-induced extracorporeal LDL precipitation (HELP). Atherosclerosis 1997, 128:241-249.
>  View the PubMed notation for this reference.
43.
 Napoli C: Decreased low-density lipoprotein oxidation after repeated selective apheresis in homozygous familial hypercholesterolemia. Am Heart J 1997, 133:585-595.
>  View the PubMed notation for this reference.
44.
 Mellwig KP: Improvement of coronary vasodilatation capacity through single LDL apheresis. Atherosclerosis 1998, 139:173-178.
>  View the PubMed notation for this reference.
45.
 Cashin-Hemphill L: Low-density lipoprotein apheresis therapy during pregnancy. Am J Cardiol 2000, 86:1160, A10.
>  View the PubMed notation for this reference.
46.
 Kroon AA: Pregnancy in a patient with homozygous familial hypercholesterolemia treated with long-term low-density lipoprotein apheresis. Metabolism 1994, 43:1164-1170.
>  View the PubMed notation for this reference.
47.
 US Food and Drug Administration, US Department of Health and Human Services: Premarket approval of Kaneka America Corporation Liposorber LA-15 System--action [Public Health Service memorandum]. Available at http://www.fda.gov/cdrh/pdf/p910018.pdf.. Accessed May 2009.
48.
 US Food and Drug Administration, US Department of Health and Human Services: Re 940016. H.E.L.P. (Heparin-induced Extracorporeal Lipoprotein Precipitation) [Public Health Service letter]. Available at http://www.fda.gov/cdrh/pdf/p940016.pdf.. Accessed May 2009.