A recent study by Dr. Banerjee, published in Circulation: Cardiovascular Interventions, demonstrated the efficacy and safety of low-density lipoprotein (LDL) lowering therapy via a single LDL apheresis treatment plus ongoing statin therapy in nonfamilial hyperlipidemia acute coronary syndrome patients treated with the percutaneous coronary intervention (PCI).
The current standard of care after acute coronary syndrome (ACS) includes intensive lipid-lowering therapy with statins that have been shown to lead to coronary atherosclerotic plaque regression and stabilization. Despite this treatment strategy, however, the incidence of recurrent ACS remains high. It is partly due to the progression or rupture of lipid-rich nonculprit atherosclerotic plaques. LDL apheresis, a nonpharmacological method of extracorporeal LDL filtration, is a known method to aggressively lower the LDL levels but is predominantly reserved for patients with familial hyperlipidemia. Another potential benefit of this procedure is the mobilization of endothelial progenitor cells (EPCs) that may contribute to vascular healing. Whether this procedure can lead to a rapid and detectable decrease in nonculprit coronary plaque volume remains unclear. The PREMIER trial (Plaque Regression and Progenitor Cell Mobilization With Intensive Lipid Elimination Regimen) is a pilot study to examine the efficacy and safety of lipid apheresis plus ongoing statin therapy in ACS patients undergoing PCI.
The PREMIER, a prospective, multicenter, randomized clinical trial, included 160 ACS patients at 4 Veterans Affairs centers. Within 72 hours of uncomplicated PCI, patients were randomized to receive either intensive lipid-lowering therapy comprising single LDL apheresis plus statin therapy or standard medical therapy with statin therapy alone. The primary efficacy endpoint of the study was the percentage change in total plaque volume at 90 days evaluated by intravascular ultrasound. The primary safety endpoint was the percentage of patients with major peri-PCI procedure adverse events. Mobilization of EPC colony-forming unit (CFU; EPC CFU/mL) of peripheral blood from baseline to 30 days and 90 days post-PCI, change in the necrotic core component of coronary plaque at 90 days, and major adverse cardiovascular events (MACEs) at 90 days and at 6-month follow-up constituted secondary efficacy endpoints of the trial. Peripheral blood sampling was performed at baseline and at 24 hours, 4 weeks, and 12 weeks post-PCI, along with a 6-month clinical follow-up. Intravascular ultrasound (IVUS) with virtual histology (VH) assessment of a ≥20-mm segment of nonculprit plaque volume was performed at baseline and 12 weeks after enrollment.
Of the 160 patients, 84 patients were included in intensive lipid-lowering therapy (ILLT) arm and 76 patients in standard statin monotherapy (SMT) arm. The prevalence of comorbidities such as diabetes mellitus, hypercholesterolemia, prior MI, and coronary revascularization was similar among the two treatment arms. 76% of ILLT participants and 80% in the SMT arms reported statin therapy before enrollment in the study (P=0.5703). Average baseline values of total cholesterol and LDL were similar, with no signifcant differences across the study groups. At the time of discharge, the mean LDL reduction was 53% in ILLT and 17% in SMT compared to baseline levels (P<0.0001 for both). Lower LDL levels were sustained in the ILLT and SMT groups at 30 days (66.4±19.6 in ILLT and 73.4±30.8 mg/dL in SMT; P<0.0001 for both) and 90 days (68.8±29.5 in ILLT and 73.2±26.3 mg/dL in SMT; P<0.0001 for both). No signifcant difference in LDL levels was reported between study groups at 30 days (P=0.10) and 90 days (P=0.34). 3 major peri-PCI adverse events was reported in ILLT participants that met the criteria for safety endpoint. No safety endpoint was reported in the SMT group. The primary efficacy endpoint of the study, on average, decreased by 4.81% in the ILLT group but increased by 2.31% in the SMT group, with a difference of -7.13% between the two treatment arms ([95% CI, -14.59 to 0.34] P=0.0611) without adjustment for covariates. Adjustment for age, preexisting coronary artery disease, diabetes mellitus, baseline LDL levels, and baseline plaque burden resulted in similar results. Robust endothelial progenitor cell colony-forming unit mobilization from baseline to 90 days was observed in the ILLT group (P=0.0015) but not in SMT (P=0.0844).
This trial was first to provide evidence for the safety and efficacy of an early and intensive lowering of LDL in patients with ACS. It particularly showed a strong regression in total plaque volume with a single LDL apheresis in addition to ongoing statin therapy. However, the small sample size, lack of power to evaluate the clinical outcomes, absence of Lp(a) and other inﬂammatory marker data, and short duration of follow-up were limiting factors that need to be considered while interpreting the results of the study. Also, the fact that the PREMIER was performed in Veterans Affairs and composed of only male participants affects the generalizability of its findings. Finally, although the observed decrease in plaque volume in the ILLT arm is promising, its sustainability and impact on future clinical outcomes remain unknown.
This trial demonstrated the safety and efficacy of a novel treatment strategy in non-familial hyperlipidemia ACS patients maintained on statin therapy. Future studies with larger sample size are required to validate the results of this study.