Lipid Apheresis

POLICY NUMBER

L.8.02.401

DESCRIPTION

This use of low-density lipoprotein (LDL) apheresis has been proposed to treat various types of familial hypercholesterolemia (FH) and other significant hyperlipidemia and to reduce atherosclerosis in cardiovascular disease. Lipid apheresis discriminately removes LDL particles from plasma while leaving other factors intact, allowing the filtrated plasma to be returned to the patient.

Hyperlipidemia

A dominantly inherited disorder, familial hypercholesterolemia results from a variant in the gene that encodes for the specific cell surface receptor responsible for low-density lipoprotein (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 LDL cholesterol levels that are approximately 2 to 3 times levels considered acceptable (i.e., >300 mg/dL). Affected male patients typically develop coronary heart disease in their thirties and forties, while women develop the disease in their fifties. Depending on the patient, heterozygous familial hypercholesterolemia may or may not respond adequately to lipid-lowering drugs.

Homozygous hypercholesterolemia is rare, occurring in only 1 in 1 million subjects. Due to the total lack of functioning LDL receptors, serum levels of LDL cholesterol may be elevated six-fold (>500 mg/dL). Homozygotes may develop severe aortic stenosis and coronary heart disease by 20 years of age. These patients typically do not adequately respond to drug or diet modification therapies. In the past, patients with homozygous familial hypercholesterolemia 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.

Treatment

Low-Density Lipoprotein

Low-density lipoprotein (LDL) apheresis (also referred to as lipid apheresis) involves the extracorporeal removal of apolipoprotein B (apo B)–containing lipoproteins, including LDL, lipoprotein(a), and very low-density lipoprotein.

The apheresis procedure is designed to isolate plasma. The low-density lipoproteins are then selectively removed from the plasma by immunoadsorption, heparin-induced extracorporeal LDL precipitation, dextran sulfate adsorption, or double-filtration plasmapheresis of lipoprotein. In immunoadsorption, polyclonal antihuman apo B antibodies from sheep selectively bind and remove LDL because apo B is the protein moiety of low-density lipoprotein. In heparin-induced extracorporeal LDL precipitation, 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 particles bound to cellulose.

High-Density Lipoprotein

High-density lipoprotein (HDL) delipidation and plasma reinfusion removes plasma from the body, processed through a delipidation device, and then returns it to the patient. The delipidation procedure selectively removes cholesterol from HDL, converting the major alpha HDL to pre-beta-like HDL, a form of HDL that enhances cholesterol transport to the liver and is thought to reduce atherosclerosis development and burden. The plasma with pre-beta-like HDL is then reinfused into the patient.

Two low-density lipoprotein (LDL) apheresis systems have been approved by the U.S. Food and Drug Administration (FDA) for marketing. In 1996, the Liposorber LA-15® System (Kaneka Pharma), dextran sulfate device, was approved by the 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 1997, the HELP® System (B. Braun), a heparin-induced extracorporeal LDL precipitation, was approved by the FDA through the premarket approval process for the same indication. FDA product code: MMY.

In 2013, the Liposorber LA-15® System was approved for additional indications through the humanitarian device exemption process for the treatment of pediatric patients with primary focal segmental glomerulosclerosis when the following conditions apply:

• "Standard treatment options, including corticosteroid and/or calcineurin inhibitor treatments, are unsuccessful or not well-tolerated, and the patient has a GFR [glomerular filtration rate] ≥60 mL/min/1.73 m² or

• The patient is post renal transplantation."

In 2020, the FDA changed the preexisting Humanitarian Use Device (HUD) 2014 designation for the Plasma Delipidation System (PDS-2™ System) to a Humanitarian Device Exemption (HDE). These regulatory pathways are intended to encourage development of devices for rare diseases. The 2020 HDE is indicated "to reduce coronary artery atheroma in adult patients with homozygous FH who are either inadequately responsive to or intolerant of maximal therapy for homozygous FH, including the latest medications and other device therapies approved by the FDA."

The modification to a HDE approval was due to safety considerations and limitations of the clinical evidence provided, which necessitated that the device use be limited to treatment of patients who are either inadequately responsive or intolerant of maximal therapy for homozygous FH. The Summary of Safety and Probable Benefit reports data on 6 patients with substantial occurrence of hypotension and bradycardia. Delipidation and reinfusion is limited to 7 treatments.

Related policies -

• Plasma Exchange

POLICY

LDL apheresis may be considered medically necessary in patients with homozygous familial hypercholesterolemia as an alternative to plasmapheresis.

LDL apheresis may be considered medically necessary in patients with heterozygous familial hypercholesterolemia who have failed 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 other uses, including nonfamilial hypercholesterolemia, nephrotic syndrome, sudden sensorineural hearing loss, severe diabetic foot ulcerations, peripheral artery disease, preeclampsia, non-arteritic acute anterior ischemic optic neuropathy, and acute coronary syndrome.

Therapeutic apheresis with selective high-density lipoprotein (HDL) delipidation and plasma reinfusion is considered investigational for all indications, including but not limited to acute coronary syndrome.

*For definitions of maximum tolerated drug therapy and documented coronary artery disease, please see Policy Guidelines.

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

A scientific statement from the American Heart Association for the treatment of heterozygous familial hypercholesterolemia (FH) has indicated that adults should be treated with available pharmacotherapy with an initial goal of reducing low-density lipoprotein cholesterol (LDL-C) by at least 50%, usually with a statin. This treatment can be followed by achieving an LDL-C of less than 100 mg/dL (absent coronary artery disease [CAD] or other major risk factors]) or 70 mg/dL (presence of CAD or other major risk factors). The following approach for pharmacotherapy is suggested:

• High-intensity statin therapy to target >50% LDL-C reduction, such as rosuvastatin or atorvastatin.

• If the patient is adherent and LDL-C is above the target goal after 3 months, consider adding ezetimibe.

• If the patient is adherent and LDL-C is above the target goal after 3 months, consider adding a PCSK9 inhibitor or colesevelam (or other bile acid sequestrant or niacin).

• If the patient is adherent and LDL-C is above the target goal after 3 months, proceed to complex therapy combination such as a 4-drug combination plus LDL apheresis.

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.

The frequency of LDL apheresis varies, but typically averages 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.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A.  consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B.  appropriate with regard to standards of good medical practice; and

C.  not solely for the convenience of the Member, his or her Provider; and

D.  the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

5/1/2008: Policy added.

9/18/2008: Annual ICD-9 updates effective 10-1-2008 applied.

4/6/2009: Policy reviewed, no changes.

09/09/2010: Policy description updated regarding treatment approaches. Policy statement unchanged.

09/28/2011: Policy reviewed; no changes.

09/27/2012: Policy reviewed; no changes.

10/22/2013: Policy reviewed; no changes.

10/21/2014: Policy title changed from "Low-Density Lipid Apheresis" to "Lipid Apheresis." Policy description updated regarding therapeutic apheresis. Added the following policy statement: Therapeutic apheresis with selective high-density lipoprotein (HDL) delipidation and plasma reinfusion is considered investigational. Policy guidelines updated regarding the frequency of LDL apheresis.

08/26/2015: Code Reference section updated for ICD-10. Removed ICD-9 procedure code 99.79.

10/22/2015: Policy description updated regarding devices. Policy statements unchanged. Policy guidelines section updated to add medically necessary and investigative definitions.

05/27/2016: Policy number A.8.02.04 added.

09/30/2016: Code Reference section updated to add new ICD-10 diagnosis codes E78.00 and E78.01.

07/07/2017: Policy description updated. Second medically necessary statement updated to remove "6-month trial." Investigational statement regarding LDL apheresis updated to include nonfamilial hypercholesterolemia, sudden sensorineural hearing loss, severe diabetic foot ulcerations, peripheral artery disease, and non-arteritic acute anterior ischemic optic neuropathy. Policy Guidelines updated to remove statement regarding maximum tolerated drug therapy and to add suggested approach for pharmacotherapy.

12/20/2017: Code Reference section updated to revise description for CPT code 36516 effective 01/01/2018. Removed deleted ICD-10 diagnosis code E78.0.

06/20/2018: Policy description updated regarding devices. Added nephrotic syndrome to investigational statement for LDL apheresis. Investigational statement regarding the use of therapeutic apheresis updated to include acute coronary syndrome as an investigational indication.

06/10/2019: Policy reviewed. Policy statements unchanged. Code Reference section updated to remove deleted CPT code 36515.

07/09/2020: Policy reviewed; no changes.

04/14/2022: Policy description updated regarding devices. Policy statement regarding LDL apheresis was updated to include acute coronary syndrome as an investigational indication. Policy Guidelines updated to change "Nervous/Mental Conditions" to "Mental Health Disorders" and "Medically Necessary" to "medical necessity." Medical policy number changed from "A.8.02.04" to "L.8.02.401."

04/25/2022: Code Reference section updated to add CPT code 0342T as investigational.

09/30/2022: Code Reference section updated to add new ICD-10 diagnosis codes I25.112, I25.702, I25.722, I25.732, I25.752, I25.762, and I25.792, effective 10/01/2022.

05/02/2023: Policy reviewed; no changes.

09/28/2023: Code Reference section updated to add new ICD-10 diagnosis code I20.89, effective 10/01/2023.

06/06/2024: Policy reviewed; no changes.

08/01/2025: Policy reviewed. Policy statements unchanged. Code Reference section updated to remove deleted ICD-10 diagnosis code I20.8.

10/01/2025: Code Reference section updated to add new ICD-10 diagnosis codes E78.010, E78.011, and E78.019.

SOURCE(S)

Blue Cross & Blue Shield Association Policy # 8.02.04

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy. 

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Covered Codes

Investigational Codes

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