Lipid Apheresis. Description

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1 Subject: Lipid Apheresis Page: 1 of 10 Last Review Status/Date: December 2014 Lipid Apheresis Description Therapeutic apheresis describes a variety of technologies used to remove select components from the plasma to treat disorders such as familial hypercholesterolemia (FH). Apheresis is a specific form of plasmapheresis that discriminately removes components, such as low-density lipoprotein (LDL) particles, from the plasma while leaving other factors intact, allowing the filtrated plasma to be returned to the patient. LDL apheresis has been investigated as a technique to treat patients with familial hypercholesterolemia (FH). Therapeutic apheresis with selective high-density lipoprotein (HDL) delipidation and plasma reinfusion has been investigated as a technique to reduce atherosclerosis in cardiovascular disease. Background Familial Hypercholesterolemia (FH) is a dominantly inherited disorder involving a mutation of the gene that encodes for the specific cell surface receptor responsible for LDL uptake by the cells. The heterozygous form affects about 1 in 500 people. The number of LDL receptors is halved in this condition, resulting in serum low-density lipoprotein cholesterol (LDL-C) levels that are approximately 2 to 3 times levels that are considered acceptable (ie, > 300 mg/dl). Affected male patients typically develop coronary heart disease in their thirties and forties, while women develop coronary heart disease in their fifties. Depending on the patient, heterozygous FH may or may not respond adequately to lipid-lowering drugs. Homozygous hypercholesterolemia is rare, only occurring in 1 in 1 million subjects. Serum levels of LDL-C may be elevated 6-fold (> 500 mg/dl), due to the total lack of functioning LDL receptors. Homozygotes may develop severe aortic stenosis and coronary heart disease by age 20 years. These patients typically do not adequately respond to drug or diet modification therapy. In the past, patients with homozygous FH may have been treated with plasma exchange, but the advent of LDL apheresis provides a more targeted approach by permitting selective removal of LDL from the plasma. The patient initially undergoes an apheresis procedure to isolate the plasma. The LDLs are then selectively removed from the plasma by either immunoadsorption, heparin-induced extracorporeal LDL precipitation (referred to as HELP), or dextran sulfate adsorption. In immunoadsorption, polyclonal antihuman apob antibodies from sheep selectively bind and remove LDL. (Apo B is the protein moiety of LDL.) In HELP, LDL and other particles containing apo B are precipitated by heparin at an acidic ph. Dextran sulfate adsorption removes LDL by binding the positively charged apo B to dextran sulfate

2 Subject: Lipid Apheresis Page: 2 of 10 particles bound to cellulose. LDL apheresis must be distinguished from plasma exchange (also referred to as plasmapheresis). In plasma exchange the plasma is collected during a pheresis procedure, then discarded and replaced with crystalloids. In contrast, LDL apheresis is a selective procedure in which only pathogenic LDLs are removed. The plasma is then returned to the patient. Therapeutic apheresis with selective HDL delipidation and plasma reinfusion is a procedure in which plasma is removed from the body by apheresis, processed through a delipidation device and then returned to the patient. The delipidation procedure selectively removes cholesterol from HDL, converting the major alpha HDL to pre-beta-like HDL. The plasma with pre-beta-like HDL is then reinfused to the patient. The pre-beta-like HDL is a form of HDL that enhances cholesterol transport to the liver and is thought to reduce atherosclerosis development and burden. Regulatory Status Two lipid apheresis systems have received approval from the U.S. Food and Drug Administration (FDA) for marketing. In February 1996, dextran sulfate device Liposorber LA-15 System (Kaneka Pharma, New York City, NY) was approved by FDA through the premarket approval process for use to acutely remove LDL-C from the plasma of high risk patient populations for whom diet has been ineffective or not tolerated. In September 2007, heparin-induced extracorporeal LDL precipitation HELP System (B. Braun, Melsungen, Germany) was approved by the FDA through the premarket approval process for use in the above indication. PMA product code: MMY There are no devices FDA approved specifically for HDL delipidation. The Lipid Sciences Plasma Delipidation System-2 by Lipid Sciences, Inc. was used in clinical studies. Lipid Sciences, Inc. ceased business operations in Policy *This policy statement applies to clinical review performed for pre-service (Prior Approval, Precertification, Advanced Benefit Determination, etc.) and/or post-service claims. LDL apheresis may be considered medically necessary in patients with homozygous familial hypercholesterolemia (FH) as an alternative to plasmapheresis. LDL apheresis may be considered medically necessary in patients with heterozygous familial hypercholesterolemia who have failed a 6-month trial of diet therapy and maximum tolerated combination drug* therapy AND who meet the following FDA-approved indications: (All LDL levels represent the best achievable LDL level after a program of diet and drug therapy.) 1. Functional hypercholesterolemic heterozygotes with LDL > 300 mg/dl 2. Functional hypercholesterolemic heterozygotes with LDL > 200 mg/dl AND documented coronary artery disease* LDL apheresis is considered investigational for all other uses, including use in preeclampsia.

3 Subject: Lipid Apheresis Page: 3 of 10 Therapeutic apheresis with selective high-density lipoprotein (HDL) delipidation and plasma reinfusion is considered investigational. *For definitions of maximum tolerated drug therapy and documented coronary artery disease, please see Policy Guidelines. Policy Guidelines Maximum tolerated drug therapy is defined as a trial of drugs from at least 2 separate classes of hypolipidemic agents such as bile acid sequestrants, HMG-CoA reductase inhibitors, fibric acid derivatives, or niacin/nicotinic acids. Documented coronary artery disease includes a history of myocardial infarction, coronary artery bypass surgery, percutaneous transluminal coronary angioplasty or alternative revascularization procedure, or progressive angina documented by exercise or non-exercise stress test. Because LDL apheresis represents a chronic, lifelong therapy, Plans may consider requiring precertification or prior approval to ensure that the patient meets the patient selection criteria. Frequency of LDL apheresis varies, but typically averages about once every 2 weeks to obtain an interapheresis level of LDL cholesterol at less than 120 mg/dl. Patients with homozygous FH may be treated more frequently. Patients are simultaneously treated with diet and drug therapy. Rationale LDL Apheresis for Familial Hypercholesterolemia (FH) This assessment is based on a 1999 TEC Assessment (1) that offered the following observations and conclusions: Three randomized controlled trials (RCTs) report that lipid apheresis is associated with clinically and statistically significantly greater reduction in low-density lipoprotein (LDL) cholesterol than that achieved by medication alone for patients with refractory hypercholesterolemia. Nonrandomized studies included patients who had failed diet and drug therapy. The efficacy of LDL lowering was of similar magnitude compared to that observed in the randomized studies. There is currently insufficient direct evidence to demonstrate that the reductions in LDL cholesterol (LDL-C) seen with LDL apheresis will result in reduced adverse cardiovascular events. However, given the established causal relationship of LDL-C and cardiac events, such an effect is likely, particularly given the fact that LDL apheresis acutely lowers the LDL cholesterol by 50 70% or more. In August 2008, the National Institute for Health and Clinical Excellence (NICE [UK]) produced a systematic review of literature on FH, including LDL apheresis in its management. (2) Although small RCTs were identified, they were not randomized to the treatment question of LDL apheresis versus other treatment but rather had apheresis in each arm. Therefore studies with lower level evidence

4 Subject: Lipid Apheresis Page: 4 of 10 confirmed the authors conclusions. They did conclude that in homozygous individuals, apheresis is relatively safe and reduces LDL but were unable to draw definitive conclusions regarding newer statin agents in conjunction, or in lieu of, apheresis. They could not form recommendations on frequency of treatments. For heterozygous individuals, the authors concluded that there was insufficient evidence to define entry criteria for apheresis treatment and recommended this intervention only in exceptional cases. LDL Apheresis for Other Indications Bianchin et al reported on the use of HELP-apheresis in the treatment of sudden sensorineural hearing loss (SSHL, which is an acute, mostly unilateral, inner ear disorder of unknown etiology), in a prospective, RCT. (3) One hundred thirty-two patients with an acute, one-sided SSNHL and a value of LDL-C greater than 120 mg/dl and/or fibrinogen greater than 320 mg/dl were randomly assigned to standard treatment, or standard treatment plus 1 session of HELP-apheresis. Standard treatment consisted of an infusion of 500 ml of glycerol, once a day for 10 days and intramuscular dexamethasone, 8 mg once a day for 10 days. Patient age range was years (average 60.4 years) for the first group and years (average 52.8 years) for the second group. In the HELPapheresis plus standard therapy group, hearing recovery was observed in 75% of patients 24 hours after treatment and in 76.4% 10 days after treatment. In the standard therapy group, the percentage of patients with hearing recovery was 41.7% after 24 hours and 45% after 10 days. The authors concluded that in patients with alterations in cholesterol and/or fibrinogen, HELP-apheresis treatment was an option in the treatment of SSHL. One study reported a case series of 11 patients with non-arteritic acute anterior ischemic optic neuropathy who were treated with 3 courses of LDL apheresis in conjunction with standard therapy of prednisone, salicylate, and pentoxiphylline. (4) All patients reported improvements in visual function, but the contribution of the LDL apheresis cannot be evaluated in this small uncontrolled trial. There are several reports of LDL apheresis use for other indications, including the treatment of small cohorts with peripheral arterial disease (5) and preeclampsia (6). Other prospective observational studies have focused on drug-resistant nephrotic syndrome (7) and lipoprotein(a) [Lp(a)] hyperlipoproteinemia in cardiovascular disease. (8) In 1 case series from Japan, 31 patients with peripheral artery disease (84% Fontaine s symptom classification II) and an average LDL of 197 mg/dl underwent mean 9.6 LDL-apheresis treatments. (5) Improvement of at least 10% for symptomatic parameters (coldness, 89%; numbness, 64%; and rest pain, 100%) was observed with no symptom worsening. Using the same 10% criterion, ankle brachial pressure index improved in 60% of limbs observed (worsened in 2%), and mean tolerated walking distance improved in 16 of 23 (70%) patients. No change was observed in any of the arterial occlusive lesions observed. A European study reported on LDL-apheresis use in preeclampsia. (6) Of the 13 patients with preeclampsia, 9 underwent between 1 and 7 heparin-mediated extracorporeal LDL precipitation (HELP) apheresis treatments and were reported to have experienced a mean 18 days (range 3 49) longer gestation. Mortality was 1 in 9 in neonates of apheresis-treated mothers and 1 in 4 in neonates of mothers not treated with apheresis. The high risk of mortality in preeclampsia and the improved perinatal outcomes that accompany longer gestation are important reasons for further study of LDL apheresis. Muso et al reported on the short-term results of LDL apheresis for drug-resistant nephrotic syndrome. (7) Proteinuria and hypoproteinemia improved with LDL apheresis allowing some patients to go into

5 Subject: Lipid Apheresis Page: 5 of 10 remission based on urinary protein levels. Leebmann et al reported on a prospective observational multicenter study of 170 patients treated with LDL apheresis for Lp(a)-hyperlipoproteinemia and progressive cardiovascular disease despite receiving maximally tolerated lipid-lowering treatment.8 During the 2-year treatment period with LDL apheresis, the authors reported a significant decrease in cardiovascular events compared with the 2-year period prior to treatment with LDL apheresis. A series of 17 patients with severe diabetic foot ulcerations were treated with LDL apheresis on the hypothesis that drastically lowered fibrinogen, and possibly lowered plasma viscosity, would improve perfusion to the ischemic tissue and facilitate wound healing. (9) Patients underwent between 1 and 7 treatments and were followed up for 2 73 months. LDL apheresis may have improved wound healing and reduced the risk of lower leg amputations; however, there was no control group or formal quantitative assessments of the lesions. While these studies lack the methodologic rigor required to add medically necessary indications to the policy statement, they suggest potential investigational uses for LDL apheresis. Larger, randomized trials of longer duration are needed to determine the impact of LDL apheresis on health outcomes in these other conditions. Therapeutic Apheresis with High-Density Lipoprotein Delipidation and Plasma Reinfusion Waksman et al reported on a safety and feasibility RCT of 28 patients with acute coronary syndrome treated with therapeutic apheresis with selective high-density lipoprotein (HDL) delipidation and plasma reinfusion. (10) Cardiac catheterization patients were randomized to receive 7 weekly therapeutic apheresis and plasma reinfusion with or without HDL delipidation. During catheterization and up to 2 weeks after the apheresis sessions were completed, intravascular ultrasound (IVUS) was performed on a target vessel. Pre-beta-like HDL and alpha HDL levels in the plasma before and after delipidation changed from 5.6% to 79.1% and 92.8% to 20.9%, respectively. IVUS showed some evidence of regression in total atheroma volume in the delipidation patients, but this was not significant. No additional studies were identified. The available evidence on therapeutic apheresis with selective HDL delipidation and plasma reinfusion is insufficient to draw conclusions. Further, larger well-designed RCTs with reports on health outcomes are needed. Ongoing Trials A search of ClinicalTrials.gov identified 1 randomized trial in which LDL apheresis will be compared with traditional treatment for diabetic foot ulcers in 132 patients (NCT ). Several nonrandomized studies were identified that will examine LDL apheresis for the treatment of nonexudative (dry) age-related macular degeneration in 20 patients (NCT ) and preeclampsia in 15 patients (NCT ) and to evaluate the safety and efficacy of the DALI (Direct Adsorption of Lipoproteins) system and the MONET (Membrane Filtration Optimized Novel Extracorporeal Treatment) system in cohorts totaling 108 patients (NCT ). No studies were identified on HDL delipidation and plasma reinfusion.

6 Subject: Lipid Apheresis Page: 6 of 10 Practice Guidelines and Position Statements In 2013, the Writing Committee of the American Society for Apheresis issued guidelines for use of apheresis in 78 conditions. (11) LDL apheresis for homozygous FH is considered first-line treatment (Category I) with a Grade IA recommendation (strong recommendation, high-quality evidence) Heterozygous FH is considered appropriate as a second-line (Category II), Grade 1A recommendation. Other indications listed for LDL apheresis in the American Society for Apheresis guidelines include: Lipoprotein (a) hyperlipoproteinemia- Category II; Grade IB strong recommendation, moderate quality evidence; Peripheral vascular diseases- Category III- optimum role not established, Grade 2C- weak recommendation, low quality evidence Phytanic acid storage disease (Refsum s disease)- Category II, Grade 2C; Sudden sensorineural hearing loss- Category III; Grade 2A- weak recommendation, high-quality evidence) In 2011, the National Lipid Association issued guidelines on the treatment of familial hypercholesterolemia. (12) This guidance recommends LDL apheresis for familial hypercholesterolemia in patients who do not adequately respond to maximum tolerated drug therapy after 6 months of treatment as follows with: Functional homozygous with LDL cholesterol 300 mg/dl (or non-hdl cholesterol 330 mg/dl); Functional heterozygous with LDL cholesterol 300 mg/dl (or non-hdl cholesterol 330 mg/dl) and 0-1 coronary heart disease risk factors; Functional heterozygous with LDL cholesterol 200 mg/dl (or non-hdl cholesterol 230 mg/dl) and high risk characteristics such as 2 risk factors or high lipoprotein (a) 50 mg/dl; or Functional heterozygotes with LDL cholesterol 160 mg/dl (or non-hdl cholesterol 190 mg/dl) and very high risk characteristics (established coronary heart disease, other cardiovascular disease, or diabetes). The 2002 Third Report of the National Cholesterol Education Program (Adult Treatment Panel III or ATP III) recommends therapeutic lifestyle changes and maximal medical therapy for heterozygous familial hypercholesterolemia patients. (13) For homozygous individuals, ATP III recommends LDL apheresis and the addition of a statin for the prevention of rebound hyperlipidemia. The American Heart Association Expert Panel on Population and Prevention Science made an additional recommendation for children diagnosed with homozygous FH: initiate apheresis treatment as soon as feasible, consider low-dose anticoagulation. For heterozygous FH, this group recommends considering statin treatment at 10 years of age for males and at puberty for females. (14)

7 Subject: Lipid Apheresis Page: 7 of 10 The Medial Advisory Secretariat of the Ministry of Health of Ontario published an evidence-based analysis of the available literature for the period of January 1998 to May (15) Of 398 identified articles, 8 studies met the inclusion criteria of having subjects with FH refractory to statins and diet therapy. Studies with interventions other than the HELP system were excluded, as HELP was the only LDL apheresis system approved at that time in Canada. Five case series, 2 case series nested within comparative studies, and 1 retrospective review, as well as a heath technology assessment conducted in Alberta, and a review by the FDA were included. The authors observed large heterogeneity among the studies, which were judged to be of low quality due to study design. Overall, the mean acute (immediately following treatment) relative decrease in LDL with HELP LDL apheresis ranged from 53% to 77%. The mean chronic (end of study) relative decrease ranged from 9% to 46%. While subjects did not reach target level of LDL in the studies, the LDL-high-density lipoprotein (HDL) and total cholesterol (TC)-HDL ratios met targeted values. The authors conclude that for homozygous FH patients, there is a strong recommendation based on low- to very low-quality evidence that the benefits of LDL apheresis outweigh risks and burdens. In contrast, the authors offer a weak recommendation based on low- to very low-quality evidence favoring apheresis for heterozygous individuals. For the small number of heterozygous individuals who are intolerant to lipidlowering medications, or who cannot reach lipid level targets on maximal diet and medication, the authors remark that LDL apheresis is likely as beneficial and less likely to have fewer adverse effects, as plasmapheresis. No guidelines on therapeutic apheresis with selective HDL delipidation and plasma reinfusion were identified. U.S. Preventive Service Task Force Recommendations No guidelines were identified. Summary Therapeutic apheresis describes a variety of technologies used to remove select components from the plasma to treat disorders such as familial hypercholesterolemia (FH). Apheresis is a specific form of plasmapheresis that discriminately removes components, such as LDL particles, from the plasma while leaving other factors intact, allowing the filtrated plasma to be returned to the patient. LDL apheresis has been investigated as a technique to treat patients with FH. Therapeutic apheresis with selective high-density lipoprotein (HDL) delipidation and plasma reinfusion has been investigated as a technique to reduce atherosclerosis in cardiovascular disease. Homozygous FH is a rare disorder. Sufficiently-powered randomized controlled trials evaluating the net benefit of LDL apheresis to these patients are unlikely to be forthcoming in the near future. Based on strong recommendations from low quality evidence, apheresis is a reasonable alternative to plasmapheresis in homozygotes who, despite maximal medical therapy, continue to maintain significantly elevated low density lipid profiles or have evidence of progressive lipid-associated complications. Therefore, LDL apheresis may be considered medically necessary in patients with homozygous familial hypercholesterolemia as an alternative to plasmapheresis.

8 Subject: Lipid Apheresis Page: 8 of 10 Heterozygous FH is less rare and evidence is less compelling to recommend apheresis. However, due to known variability of severity of lipid disorders with this condition, apheresis is a reasonable strategy in these patients to reduce LDL levels to reduce atherosclerotic risk when, despite maximal medical therapy over six months, LDL remains above 300 mg/dl in asymptomatic individuals, or above 200 mg/dl in patients with known coronary artery disease. Therefore, LDL apheresis may be considered medically necessary in patients with heterozygous familial hypercholesterolemia with the above listed criteria. At this time, the data are insufficient to determine the impact of LDL apheresis on health outcomes for other investigational uses (e.g., preeclampsia, treatment of diabetic foot ulcers). Data on therapeutic apheresis with selective HDL delipidation and plasma reinfusion is limited to 1 RCT on safety and feasibility. This RCT reported improvements in intermediate outcomes; however, data are insufficient to determine the impact of therapeutic apheresis with selective HDL delipidation and plasma reinfusion on health outcomes. Medicare National Coverage Decision National Coverage Decision APHERESIS (therapeutic pheresis) lists the indications for which apheresis is a covered benefit in cellular and immune-complex mediated disorders. There is no determination for hypercholesterolemia or LDL apheresis. (16) References 1. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Lipid apheresis in the treatment of severe, refractory hypercholesterolemia. TEC Assessments 1999; Volume14, Tab 3. PMID 2. National Institute for Health and Clinical Excellence (NICE). National Collaborating Centre for Primary Care. Identification and management of familial hypercholesterolaemia. London (UK): 2008 Aug. 45 p. (Clinical guideline; no. 71). PMID Bianchin G, Russi G, Romano N et al. Treatment with HELP-apheresis in patients suffering from sudden sensorineural hearing loss: a prospective, randomized, controlled study. Laryngoscope Apr 2010; 120(4): PMID Ramunni A, Giancipoli G, Guerriero S et al. LDL-apheresis accelerates the recovery of nonarteritic acute anterior ischemic optic neuropathy. Ther Apher Dial Feb 2005; 9(1):53-8. PMID Tsuchida H, Shigematsu H, Ishimaru S et al. Effect of low-density lipoprotein apheresis on patients with peripheral arterial disease. Peripheral Arterial Disease LDL Apheresis Multicenter Study (P-LAS). Int Angiol Sep 2006; 25(3): PMID Wang Y, Walli AK, Schulze A et al. Heparin-mediated extracorporeal low density lipoprotein precipitation as a possible therapeutic approach in preeclampsia. Transfus Apher Sci Oct 2006; 35(2): PMID

9 Subject: Lipid Apheresis Page: 9 of Muso E, Mune M, Hirano T, et al. Immediate therapeutic efficacy of low-density lipoprotein apheresis for drug-resistant nephrotic syndrome: evidence from the short-term results from the POLARIS Study. Clin Exp Nephrol. Jun PMID Leebmann J, Roeseler E, Julius U, et al. Lipoprotein apheresis in patients with maximally tolerated lipid-lowering therapy, lipoprotein(a)-hyperlipoproteinemia, and progressive cardiovascular disease: prospective observational multicenter study. Circulation. Dec ; 128(24): PMID Rietzsch H, Panzner I, Selisko T et al. Heparin-induced extracorporal LDL precipitation (H.E.L.P) in diabetic foot syndrome - preventive and regenerative potential? Horm Metab Res Jul 2008; 40(7): PMID Waksman R, Torguson R, Kent KM, et al. A first-in-man, randomized, placebo-controlled study to evaluate the safety and feasibility of autologous delipidated high-density lipoprotein plasma infusions in patients with acute coronary syndrome. J Am Coll Cardiol. Jun ; 55(24): PMID Schwartz J, Winters JL, Padmanabhan A, et al. Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the Writing Committee of the American Society for Apheresis: the sixth special issue. J Clin Apher. Jul 2013; 28(3): PMID Goldberg AC, Hopkins PN, Toth PP et al. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol Jun 2011; 5(3 Suppl):S1-8. PMID National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the Adult Treatment Panel. NIH Publication No Available online at: Last accessed August Kavey RE, Allada V, Daniels SR et al. 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 Dec ; 114(24): PMID Medical Advisory Secretariat. Low density lipoprotein apheresis: an evidence-based analysis. Ontario Health Technology Assessment Series 2007; 7(5). PMID 16. Centers for Medicare and Medicaid Services. National Coverage Determination (NCD) for APHERESIS (Therapeutic Pheresis) (110.14). Available online at: Last accessed August 2014.

10 Subject: Lipid Apheresis Page: 10 of 10 Policy History Date Action Reason December 2011 New Policy Policy created with literature search. December 2012 Update Policy Literature search, no new references added; no change in policy statements. December 2013 Update Policy Policy updated with literature search; reference 8 added no change in policy statements. December 2014 Update Policy Policy updated with literature review; references 7-8 and added; added policy statement indicating therapeutic apheresis with selective high-density lipoprotein (HDL) delipidation and plasma reinfusion is investigational; title change to Lipid Apheresis Keywords Apheresis, LDL Familial Hypercholesterolemia, Apheresis Hypercholesterolemia, Apheresis LDL Apheresis This policy was approved by the FEP Pharmacy and Medical Policy Committee on December 5, 2014 and is effective January 15, Signature on File Deborah M. Smith, MD, MPH