LDL-apheresis as an alternate method for plasma LPS purification in healthy volunteers, dyslipidemic and septic patients

Lipopolysaccharide (LPS) is a key player for innate immunity activation. It is therefore a prime target for sepsis treatment, as antibiotics are not sufficient to improve outcome during septic shock. Extracorporeal removal method by polymyxin B hemoperfusion (PMX-DHP) is used in Japan, but recent trials failed to show a significant lowering of circulating LPS levels after PMX-DHP therapy. PMX-DHP has a direct effect on LPS molecules. However, LPS is not present in a free form in the circulation, as it is mainly carried by lipoproteins, including low density lipoproteins (LDL). Lipoproteins are critical for physiological LPS clearance, as LPS are carried by low density lipoproteins (LDL) to the liver for elimination. We hypothesized that LDL-apheresis can be an alternate method for LPS removal. We demonstrated first in vitro that LDL apheresis microbeads are almost as efficient as PMX beads to reduce LPS concentration in LPS-spiked human plasma, whereas it is not active in phosphate-buffered saline. We found that PMX was also adsorbing lipoproteins, although less specifically. Then, we found that endogenous LPS of patients treated by LDL-apheresis for familial hypercholesterolemia is also removed during their LDL-apheresis sessions, both with electrostatic-based devices and filtration devices. Finally, LPS circulating in the plasma of septic shock and severe sepsis patients with gram-negative bacteremia was also removed in vitro by LDL adsorption. Overall, these results underline the importance of lipoproteins for LPS clearance, making them a prime target to study and treat endotoxemia-related conditions.

LDL apheresis as an alternate method for plasma LPS purification in healthy volunteers and dyslipidemic and septic patients

Lipopolysaccharide (LPS) is a key player for innate immunity activation. It is therefore a prime target for sepsis treatment, as antibiotics are not sufficient to improve outcome during septic shock. An extracorporeal removal method by polymyxin (PMX) B direct hemoperfusion (PMX-DHP) is used in Japan, but recent trials failed to show a significant lowering of circulating LPS levels after PMX-DHP therapy. PMX-DHP has a direct effect on LPS molecules. However, LPS is not present in a free form in the circulation, as it is mainly carried by lipoproteins, including LDLs. Lipoproteins are critical for physiological LPS clearance, as LPSs are carried by LDLs to the liver for elimination. We hypothesized that LDL apheresis could be an alternate method for LPS removal. First, we demonstrated in vitro that LDL apheresis microbeads are almost as efficient as PMX beads to reduce LPS concentration in LPS-spiked human plasma, whereas it is not active in PBS. We found that PMX was also adsorbing lipoproteins, although less specifically. Then, we found that endogenous LPS of patients treated by LDL apheresis for familial hypercholesterolemia is also removed during their LDL apheresis sessions, with both electrostatic-based devices and filtration devices. Finally, LPS circulating in the plasma of septic shock and severe sepsis patients with gram-negative bacteremia was also removed in vitro by LDL adsorption. Overall, these results underline the importance of lipoproteins for LPS clearance, making them a prime target to study and treat endotoxemia-related conditions.

Is LDL apheresis a thing of the past?

Patients with severe hypercholesterolaemia have a high lifetime risk for developing cardiovascular disease. These patients are traditionally treated with high-intensity statins and ezetimibe. Some patients are refractory to treatment and cannot achieve a desirable reduction in low-density lipoprotein cholesterol (LDL-C). LDL apheresis or lipoprotein apheresis (LA) is a radical treatment which involves the intermittent extracorporeal removal of atherogenic apolipoprotein B-100-containing lipoproteins from the systemic circulation. The procedure requires the use of highly specialised equipment and is carried out under medical supervision for patients with severe hypercholesterolaemia, refractory to treatment with high-intensity statins and ezetimibe. The advent of targeted therapies, including monoclonal antibodies and gene silencing therapies, offer treatment options that could replace LA for these patients. Large scale clinical trials for the PCSK inhibitors evolocumab and alirocumab show favourable outcomes in terms of lipid lowering, with a 50% to 60% improvement in baseline LDL-C levels. This suggests that these therapies could reduce the need for LA in patients with hypercholesterolaemia. This review describes the main clinical trials for the PCSK inhibitors and discusses the place of these therapies in the management of severe hypercholesterolaemia. While these new therapies show promise as an effective option for lowering LDL-C levels in patients refractory to conventional treatment and have added benefits of ease of administration and compliance to treatment, long-term safety data is still needed. Favourable safety data could relegate the use of LA for a select few patients who may not tolerate the new therapies.

Plaque Regression and Endothelial Progenitor Cell Mobilization With Intensive Lipid Elimination Regimen (PREMIER)

Background: Low-density lipoproteins (LDLs) are removed by extracorporeal filtration during LDL apheresis. It is mainly used in familial hyperlipidemia. The PREMIER trial (Plaque Regression and Progenitor Cell Mobilization With Intensive Lipid Elimination Regimen) evaluated LDL apheresis in nonfamilial hyperlipidemia acute coronary syndrome patients treated with percutaneous coronary intervention. Methods: We randomized 160 acute coronary syndrome patients at 4 Veterans Affairs centers within 72 hours of percutaneous coronary intervention to intensive lipid-lowering therapy (ILLT) comprising single LDL apheresis and statins versus standard medical therapy (SMT) with no LDL apheresis and statin therapy alone. Trial objectives constituted primary safety and primary efficacy end points and endothelial progenitor cell colony-forming unit mobilization in peripheral blood. Results: Mean LDL reduction at discharge was 53% in ILLT and 17% in SMT groups ( P <0.0001) from baseline levels of 116.3±34.3 and 110.7±32 mg/dL ( P =0.2979), respectively. The incidence of the primary safety end point of major peri-percutaneous coronary intervention adverse events was similar in both groups (ILLT, 3; SMT, 0). The primary efficacy end point, percentage change in total plaque volume at 90 days by intravascular ultrasound, on average decreased by 4.81% in the ILLT group and increased by 2.31% in the SMT group (difference of means, −7.13 [95% CI, −14.59 to 0.34]; P =0.0611). The raw change in total plaque volume on average decreased more in the ILLT group than in the SMT group (−6.01 versus −0.95 mm 3 ; difference of means, −5.06 [95% CI, −11.61 to 1.48]; P =0.1286). Similar results were obtained after adjusting for participating sites, age, preexisting coronary artery disease, diabetes mellitus, baseline LDL levels, and baseline plaque burden. There was robust endothelial progenitor cell colony-forming unit mobilization from baseline to 90 days in the ILLT group ( P =0.0015) but not in SMT ( P =0.0844). Conclusions: PREMIER is the first randomized clinical trial to demonstrate safety and a trend for early coronary plaque regression with LDL apheresis in nonfamilial hyperlipidemia acute coronary syndrome patients treated with percutaneous coronary intervention. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01004406 and NCT02347098.