Introduction
Hypercholesterolemia significantly raises atherosclerotic cardiovascular disease (ASCVD) risk, with higher and prolonged elevations in low-density lipoprotein (LDL) cholesterol (LDL-C), non–high-density lipoprotein (non-HDL) cholesterol (non-HDL-C), remnant lipoproteins, and lipoprotein(a) (Lp(a) levels linked to increased ASCVD risk.
In familial hypercholesterolemia (FH), severe lifelong LDL-C elevation leads to high ASCVD risk. Despite various treatments, many FH patients need additional LDL-C lowering, where lipoprotein apheresis (LA) is beneficial.
Lp(a) is an atherogenic lipoprotein with apoB linked to increased risks of ASCVD, arterial thrombosis, and calcific aortic stenosis (AS). Mendelian randomization shows elevated Lp(a) raises ASCVD risk six-fold. Besides lipoprotein apheresis (LA), effective Lp(a)-lowering options are limited. Though specific cardiovascular benefits are not proven, lowering Lp(a) with LA reduces ASCVD risk and may benefit kidney disease in some patients with refractory focal segmental glomerulosclerosis (FSGS) and preeclampsia
Potential Role of LA in Management of Familial Hypercholesterolemia
Adults with heterozygous FH (HeFH) often have untreated LDL-C levels of 190–450 mg/dL, carrying a 50% ASCVD event risk by age 50 in men and 65 in women if untreated. Pediatric and adult patients with homozygous FH (HoFH) typically show untreated LDL-C of 450–1100 mg/dL, with ASCVD events beginning around age 12 (mean) and death by 18 if untreated.
HeFH patients typically respond to LDLR-based lipid-lowering therapy, but HoFH patients, with little to no LDLR activity, respond less effectively. Patients with refractory hypercholesterolemia in both groups may consider lipoprotein apheresis (LA) for primary and secondary ASCVD prevention.
Lifestyle modification is the cornerstone of lipid-lowering. Due to their safety and efficacy, statins are the first line for LDL-C reduction, but they rarely achieve target levels in HeFH and never in HoFH. Adjunctive therapies (e.g., ezetimibe, and PCSK9 inhibitors) help but often remain insufficient, especially in HoFH.
Two LDLR-independent drugs, lomitapide and evinacumab, are approved only for HoFH. Lomitapide reduces hepatic synthesis and production of very-low-density lipoproteins (VLDL), while evinacumab promotes clearance of VLDL and intermediate-density lipoprotein. Both are costly and lack strong ASCVD prevention data.
Lomitapide (20-40% LDL-C reduction) and evinacumab (49% reduction) can reduce LDL-C, but many patients remain above LDL-C targets despite combination therapies, and some may experience side effects. Liver transplantation is rarely used for severe refractory HoFH, while gene therapy for HoFH is in early development.
Lipoprotein apheresis (LA) effectively lowers LDL-C and Lp(a). It is FDA-approved for FH patients after lifestyle and maximal medication efforts at specific LDL-C thresholds (LDL-C level >100 mg/d). LA is underused for high-risk patients needing better lipoprotein control despite its benefit.
Development, Indications, Efficacy, and Effects of LA
LA Development
In 1981, LDL particle removal using a cell separator and immunoadsorbent column was introduced. This method was later replaced by techniques involving perfusion of anticoagulated plasma through affinity columns with dextran sulfate (DS) or polyacrylate-coated beads, which adsorb the apoB component of LDL and Lp(a), removing them.
Other LA methods include heparin-induced extracorporeal LDL precipitation and double-filtration plasmapheresis. DS adsorption and polyacrylate/polyacrylamide adsorption of apoB-containing lipoproteins from whole blood (hemoperfusion) are popular in the UK. The FDA approved DS adsorption of plasma and heparin-induced extracorporeal LDL precipitation but not hemoperfusion.
LA Indications
The LIPOSORBER LA-15 system is approved for patients with HoFH (LDL-C >500 mg/dL), HeFH (LDL-C ≥300 mg/dL), or HeFH (LDL-C ≥100 mg/dL, Lp(a) ≥60 mg/dL, and coronary artery disease/peripheral artery disease) when diet and maximum drug therapy are ineffective or intolerable.
Efficacy of LA for Lowering LDL-C and Lp(a)
LDL-C levels can decrease by up to 85% after treating approximately two plasma or blood volumes with LA. Frequent procedures lead to greater reductions in time-averaged LDL-C levels, as levels rebound quickly after treatment.
When performed biweekly, mean time-averaged LDL-C reduction is 35% in HoFH and 22% in HeFH. Weekly LA reduces (interval mean values) LDL-C by 46% in HoFH and 31% in HeFH, with greater reductions in HoFH due to slower LDL rebound. Weekly LA combined with multidrug therapy can reduce the time-averaged LDL-C concentration by 70-80% in HoFH. Lp(a) reduction with LA was similar to LDL-C reduction.
Vascular Effects of LA
Lipoprotein apheresis (LA) improves biomarkers and vascular function, with increased nitric oxide production and vasodilation and reduced MCP-1 (monocyte chemoattractant protein-1), VCAM-1, endothelin, blood viscosity, fibrinogen, von Willebrand factor, and several coagulation factors. LA also decreases oxidized and small dense LDL, interleukins, TNF-α, high-sensitivity CRP, and Lp-PLA2. However, the direct link between these alterations and improved outcomes independent of lipoprotein lowering remains unclear.
Effects of LA on High-Density Lipoprotein Cholesterol
Due to its negative isoelectric charge, only a small percentage of HDL particles are removed during LA, with HDL-C levels returning to baseline in 1–2 days. HDL particle concentration, possibly a better ASCVD risk predictor than total HDL-C levels, increases after LA.
Effects of LA on Plasma Inflammatory Markers
LA reduces plasma inflammation markers over both short- and long-term, along with decreased arterial inflammation markers.
Effects of LA on Blood Rheology
Elevated blood viscosity is a known independent risk factor for CVD and dementia. LA effectively lowers blood viscosity, as well as red blood cell aggregation and deformability.
Effects of LA on Extravascular Cholesterol Deposits
Severe lifelong LDL-C elevation in FH leads to subcutaneous and tendon xanthomas, often in Achilles tendons, limiting mobility. Xanthoma regression occurs slowly with substantial LDL-C reduction. Decreased xanthoma severity may correlate with reduced non-calcified arterial plaque. However, corneal arcus, which occurs due to LDL and apoB deposits in peripheral corneal stroma, remains largely unchanged by LA due to avascular composition of the cornea.
ASCVD Outcomes with LA
Uncontrolled studies comparing ASCVD event rates before and after LA suggest a 50% to 85% reduction in events post-treatment. These significant benefits likely stem from both lipid and non-lipid mechanisms.
In a nonrandomized study of 130 Japanese HeFH patients with CAD, combination therapy (LA + cholesterol-lowering drugs) reduced LDL-C by 58%, compared to 28% with drugs alone. Coronary event rates were 72% lower with combination therapy.
A 2015 retrospective study reported that after a mean duration of 6.8 years of apheresis, MACEs incidence was 79.7% lower than it was 6.4 years before treatment.
The 2022 GLAR study examined 2028 patients with elevated LDL-C or Lp(a). Over 5 years of LA, MACEs were 74% lower, and major non-coronary events were 66% lower compared to the 1–2 years before LA.
In patients with elevated Lp(a) and LDL-C, LA reduced MACEs by 60–90%. GLAR data showed an 85% reduction in MACEs and a 63% reduction in non-coronary events. Benefits with LA were greatest in patients with high Lp(a) but normal LDL-C, with an 88% reduction in MACEs and a 73% reduction in non-coronary events.
The 2013 Pro[a]LiFe study reported a reduction in annual MACE rates from 0.41±0.45 during 2 years before the LA to 0.090.09±0.22 after two years of LA—a 78% reduction (P<0.0001).
A 2017 study reported that in patients with either higher LDL-C >100 mg/dL, higher Lp(a) >60 mg/dL, or both, the group with elevated Lp(a) level reported the highest MACE rate at baseline during 2 years prior to apheresis. The same group reported the greatest relative reduction in the events during 2 years of LA (77% reduction compared with 74% reduction in a group with elevated LDL-C and Lp(a) and 53% reduction in a group with high LDL-C level.
Other Potential Indications of LA
Plaque Regression
Smaller studies on LA show that reducing LDL or Lp(a) leads to coronary plaque regression, with decreased mean stenosis in patients undergoing LA.
The LACMART study in Japan found that in 17 FH patients, statin+LA treatment led to an increase in minimal lumen diameter, while statins alone caused a decrease (minimal lumen diameter 0.12±0.43 mm with statin+LA versus −0.08±0.45 mm with statin alone; P<0.004). In 30 patients with Lp(a) >50 mg/dL, there was a 2% reduction in luminal stenosis with Lp(a) apheresis, compared to a 3.5% increase with atorvastatin alone.
Myocardial Microperfusion
Lipoprotein apheresis (LA) reduces angina in refractory cases. A randomized trial involved 20 patients to LA or sham apheresis and then crossed over. LA lowered LDL-C and Lp(a), increased myocardial perfusion reserve by 0.63 (P<0.001), improved 6-minute walk distance by 17% (67 meters; P<0.001), and improved other measures. Another trial showed improved and normalized myocardial microvascular perfusion immediately after LA.
Lower-Extremity ASCVD
LA benefits patients with lower-extremity ASCVD, a condition with historically low treatment uptake and poor outcomes. A registry showed significant improvements in claudication, walking distance, ankle-brachial index, and revascularization rates (all P<0.001) after starting weekly LA.
Studies indicate LA improves endothelium-dependent vasodilation, and case series show enhanced wound healing in patients with intractable skin ulcers caused by peripheral artery occlusion, especially with elevated Lp(a) levels.
AS (Valvular and Supravalvular)
Valvular and supravalvular AS are linked to familial hypercholesterolemia (FH) and elevated Lp(a) levels. It has been reported that lipid apheresis (LA) combined with statin therapy significantly reduced AS incidence compared to the prestatin era, while statins alone were ineffective.
LA in Pediatric Patients
LA is a safe, effective LDL-lowering treatment for HoFH patients as young as 2, achieving similar LDL-C and Lp(a) reduction similar to adults with treatment involving DS adsorption sessions every 1 to 2 weeks. Although the serious adverse events are rare, a minimum 15 kg body weight is advised due to extracorporeal volume and risk of hypotension.
Evaluating the aortic valve/root area and coronary artery openness is essential before initiating LA due to heightened hypotension and myocardial ischemia risks. Peripheral venipuncture offers the safest venous access; however, this method can be challenging in children due to smaller veins and limited cooperation with needle and catheter insertion.
Early LA treatment in HoFH patients with low on-treatment LDL-C levels improves cardiovascular event-free survival. LA may regress xanthomas and coronary/aortic plaques, though high LDL-C (above goal) still risks ASCVD events. Children with HoFH, elevated Lp(a), or stroke history particularly benefit from LA.
LA and Pregnancy
Managing lipid disorders in pregnancy and lactation is challenging due to elevated estrogen, which raises LDL-C and triglycerides. Most lipid-lowering drugs are halted during this period, except bile-acid sequestrants and possibly statins. Though clinical trials are lacking, case studies show LA to be a safe, effective LDL-C reduction method for pregnant or breastfeeding women with severe ASCVD or familial hypercholesterolemia.
In women with recent ASCVD events, thorough cardiovascular stability assessment is essential to protect both mother and fetus and address risks from not performing LA. Preliminary findings indicate that off-label LA treatment may lessen the risk and severity of preterm preeclampsia.
LA for FSGS
In the 1980s, LA was first applied to treat FSGS linked to dyslipidemia, showing potential efficacy for some patients. In pediatric FSGS cases (age 2–18), 11 publications document LA's potential benefit for 40 patients, with somewhat better responses than adults. Proteinuria outcomes show 58% achieving complete remission, 15% partial benefit, and 27% minimal benefit. GFR remained normal or normalized in 77% of cases, with 23% unchanged.
LA can enhance kidney function in certain FSGS patients, even those who do not respond to medications or experience relapse. Benefits are more likely in younger patients, those using glucocorticoids, those with shorter FSGS duration, and those with higher kidney function. The FDA has granted humanitarian device exemption for LA in adults and children with primary FSGS and nephrotic syndrome unresponsive to corticosteroids or calcineurin inhibitors or those with post-transplant recurrence in patients with a GFR ≥45 mL/min/1.73 m2.
In certain cases, a brief LA regimen—typically twice a week for 3 weeks, followed by weekly treatments for 6 weeks, totaling 12 sessions over 9 weeks—can lead to long-term remission of a serious condition that would otherwise be difficult to treat.
Implementation of LA in Practice
LA Center Availability
While countries like Germany have numerous LA centers with significant patient capacity, many others lack access to this treatment. Therefore, there is a need to increase referrals to existing centers and establish additional facilities to improve the availability and accessibility of LA procedures.
Establishing an LA Center
Setting up an LA center involves basic but essential elements. These include skilled nursing staff, sufficient space with a hospital bed or recliner for treatments, LA equipment, necessary supplies, and a system for patient referrals. Nurses with dialysis or apheresis experience can be efficiently trained for LA.
Once a patient is considered a potential candidate for LA, the following steps should be taken: confirm that all applicable medications have been tried, ensure the patient meets the criteria set by regulatory bodies like the FDA (or equivalent agencies in other countries), discuss the procedure's benefits, risks, and costs with the patient, secure insurance approval, and evaluate venous access.
Effective administrative support is crucial for establishing and running an LA center. Initial reluctance may arise due to unfamiliarity with the process, but thorough discussions highlighting the specific needs of high-risk patients with severe FH or elevated Lp(a), alongside the advantages of LA for these individuals, can help address these concerns.
Venous Access
Some patients can reliably receive LA treatments using their native veins for both blood intake and return. In adults, this typically needs 16- or 18-gauge venous access in each arm to maintain sufficient blood flow rates, as slower flows extend treatment duration.
If native veins are inadequate, alternatives include implanting high-flow central venous ports under the skin in the upper chest (e.g., Bard or Vortex), using a dual-lumen tunneled central venous catheter, or surgically creating an arteriovenous fistula in the forearm, which requires 6 to 8 weeks for maturation before it can be used for LA.
Determining the optimal approach for each patient requires collaborative decision-making and a thorough understanding of the advantages and disadvantages of each option. Central lines, while beneficial, carry an increased risk of infection and sepsis, especially in children. When not used regularly for LA, both central lines and ports must be flushed with heparin between treatments. Percutaneous central lines typically require at least weekly flushes, which means flushing is needed between biweekly LA sessions.
Cost-Effectiveness of DS LA for Prevention of ASCVD
The cost-effectiveness of LA for reducing ASCVD events can be estimated by comparing findings from the largest study on ASCVD outcomes in LA-treated patients with those from the most extensive ASCVD outcomes trial involving evolocumab, the widely used PCSK9 inhibitor.
Patient Perspective
The published research does not detail the challenges faced by patients undergoing LA. Information on patient retention, quality-of-life impacts, and approaches for enhancing long-term adherence is sparse. Existing studies involve small participant groups, lack stratification by underlying conditions, and primarily focus on individuals with HoFH rather than the more prevalent HeFH patients, limiting the applicability of these findings.
A study's findings suggested that treatment-related QoL significantly affects health-related QoL and physical complaints in LA patients, indicating that further research and QoL screenings may support personalized care.
Another study identified several burdens of LA therapy, including biweekly sessions, work disruptions, cost, invasiveness, insurance concerns, and limited facility access. In the U.S., only 33 states have LA centers, requiring some patients to travel longer distances for treatment.
