Treating PAD Patients with Lipoprotein Apheresis

See article vol. 31: 1370-1385

Lipoprotein apheresis was developed to treat patients with homozygous familial hypercholesterolemia (HoFH) who do not respond to lipid-lowering drugs requiring LDL receptor function, such as statins. Since then, lipoprotein apheresis has been the mainstream treatment for treating HoFH patients^{1, 2)}. A large amount of LDL can be removed by lipoprotein apheresis, leading to the improvement of coronary artery stenosis and regression of xanthomas, accompanied by a reduction in LDL-C³⁾. Later, this therapeutic approach was indicated for severe heterozygous FH (HeFH), in which LDL-C levels did not decrease to the target LDL-C level by the maximal tolerated dose of statins and ezetimibe³⁾.

As the dextran sulfate cellulose bead columns used for lipoprotein apheresis have a negative charge, substances that have a positive charge can be bound, such as apolipoprotein B-containing lipoproteins. Lp(a), also known as an atherogenic lipoprotein and an independent risk factor, can also be bound and removed by lipoprotein apheresis. Importantly, Lp(a) which cannot be significantly decreased by any lipid-lowering drugs except for Lp(a)-targeted nucleic acid drugs that are currently under development. In addition to atherogenic lipoproteins, inflammatory cytokines, including tumor necrosis factor (TNF)-α and interleukin 1β, coagulation factors such as fibrinogen, and thrombosis factors were also removed by lipoprotein apheresis, which may contribute to the prevention of atherosclerosis in addition to the removal of atherogenic lipoproteins⁴⁾.

In the present paper, the efficacy of Liposorber^® was evaluated in 30 normolipidemic patients with conventional treatment-resistant PAD to evaluate the efficacy of Liposorber^{® 5)}. After 1 month of treatment, the ABI, total VascuQOL score, and most of the domain scores of VascuQOL improved. More than half of the patients with ulcers showed complete epithelialization. Serum TC, LDL-C, triglyceride, CRP, and plasma fibrinogen levels did not change significantly from baseline, while HDL-C levels showed a significant increase. No significant correlations were observed between the changes in ABI and RHI, between ABI or VascuQOL and dROMs or BAP.

Many reports have described the favorable effect of lipoprotein apheresis in PAD patients from Japan and other countries⁶⁾. Lipoprotein apheresis with Liposorber is indicated for PAD patients with hypercholesterolemia in Japan. In the present paper, normolipidemic PAD patients were enrolled despite them not being indicated for lipoprotein apheresis treatment in Japan, suggesting that lipoprotein apheresis treatment is effective not only in hypercholesterolemia patients but also in normolipidemic patients. The authors stated that the main mechanism of the effect of Liposorber^® in PAD patients is not the removal of LDL, rather, it is the removal of other factors.

Recently, an adsorptive blood purifier Rheocarna^®, which was developed to improve blood rheology, became available for PAD patients with normolipidemia⁷⁾. The adsorptive blood purifier of Rheocarna^® is immobilized with negatively charged dextran sulfate and hydrophobic tryptophan to remove LDL and fibrinogen. A comparison of the characteristics of Rheocarna^® and Liposorber^® is presented in Table 1. Rheocarna^® does not require plasma separation, and its circuit is simpler and easier to handle than Liposorber^®. In contrast, Liposorber^® is covered by insurance for patients with Fontaine II–IV with TC ≥ 220 mg/dL or LDL-C ≥ 140 mg/dL, while Rheocarna^® is covered by insurance for Fontaine IV patients. The reduction rates of LDL-C and fibrinogen levels after each treatment are shown in Table 2. Rheocarna^® showed a greater decrease in fibrinogen than in LDL. Although there have been few reports regarding the factors that were removed by Rheocarna^®, many proteins are considered to be removed owing to the characteristics of the column. More data are needed to address the efficacy of PAD. However, Rheocarna^® is a favorable option for the treatment of PAD.

Table 1. Comparison of characteristics between Rheocarna^® and Liposorber^®

	Rheocarna®	Liposorber®
Circulation method	Direct blood perfusion method	Plasma perfusion method
Adsorption target	LDL and Fibrinogen	LDL
Plasma separator	None	Membrane type plasma separator Sulfrax
Plasma purifier	None	KANEKA MA-03
Circuit	Simplified	Complex
Purpose of use	Improvement of ulcers in ASO patients who are not suitable for revascularization	To remove apolipoprotein B-containing lipoproteins from isolated plasma
Patients covered by insurance	ASO patients with Fontein classification IV	ASO patients with Fontaine classification II–IV accompanied by hyperlipidemia (TC ≥ 220 mg/dL or LDL-C ≥ 140 mg/dL)

Table 2. comparison of efficacy between Rheocarna^® and Liposorber^{® 8, 9)}

	Rheocarna®	Liposorber®
Reduction rate of LDL-C (%)	20	60
Reduction rate of fibrinogen (%)	20	20

Conflicts of Interest

Mariko Harada Shiba holds stocks in Liid Pharmaceuticals and receives payments or honoraria from Amgen, MEDPACE, Novartis, Protosera, BML, and Kowa.

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