Coronary plaques that are prone to rupture and lead to adverse cardiac events are characterized by large plaque loads, high lipid content, and thin fiber caps. Numerous studies have confirmed that statins can be effective in stopping the progression of coronary atherosclerosis.
Pro-protein invertase subtillin 9 (PCSK9) inhibitors are also a class of lipid-lowering drugs that have received a lot of attention in recent years.
According to the data provided in the "Guidelines for the Primary Diagnosis and Treatment of Dyslipidemia (2019)" released in 2019, PCSK9 inhibitors are currently known to have a strong cholesterol-lowering effect, which can reduce LDL-C by 50% to 70%.
So if a PCSK9 inhibitor is added to statin therapy, how will it affect plaque load and composition? Such a study was published at the 71st Annual Scientific Meeting of the American College of Cardiology (ACC.22).
The double-blind PACMAN-AMI study evaluated the effect of the PCSK9 inhibitor alirocumab on coronary atherosclerosis in patients undergoing percutaneous coronary intervention (PCI) due to acute myocardial infarction (AMI), and provided the effect of aliciclimab on plaque morphology and volume in such patients who need to be intensively lowered lipids from an imaging perspective. The findings were published simultaneously in the Journal of the American Medical Association (JAMA).
Screenshot source: JAMA
The PACMAN-AMI study was a double-blind, placebo-controlled, randomized clinical trial enrolling 300 patients with PCI for acute myocardial infarction from May 9, 2017 to October 7, 2020, followed up until October 13, 2021.
Enrolled patients were randomly assigned to either the aliciclizumab group (150 mg, n=148) or placebo group (n=152) once every two weeks after PCI, and the enrolled patients received high-intensity statin therapy (rosuvastatin, 20 mg).
At baseline and at 52 weeks, two non-infarction-associated arteries were tested continuously with intravascular ultrasound (IVUS), near-infrared spectroscopy (NIRS), and optical coherence tomography (OCT).
The primary endpoints of the study were the change in the percentage of atherosclerosis volume measured by IVUS; the two secondary endpoints were the change in the maximum lipid core load index measured by NIRS and the minimum fiber cap thickness measured by OCT.
Continuous imaging of 537 blood vessels in 265 (88.3%) of 265 (88.3%) patients was performed for 300 randomized patients [mean age 58.5 years; 56 (18.7%) women; mean LDL cholesterol levels] included in the study.
The main result
Atherosclerotic volume percentage
At 52 weeks, the average change in atherosclerotic volume percentage in the Aliszeumab group was -2.13% and -0.92% in the placebo group [1.21% difference between groups (95% CI, 1.78% to 0.65%), P
Maximum lipid core load index within 4 mm
The mean change in the maximum lipid core load index within 4 mm of Alisclimumab was -79.42; in the placebo group was -37.60 [group difference 41.24 (95% CI, 70.71 to 11.77); P=0.006]。
Minimum fiber cap thickness
The mean change in the minimum fiber cap thickness in the Alissidimab group was 62.67 μm, compared with 33.19 μm in the placebo group [difference between groups 29.65 μm (95% CI, 11.75-47.55); P=0.001]。
The incidence of adverse events in patients in the Aliszemab group was 70.7% and 72.8% in the placebo group.
Conclusions of the study
In patients with acute myocardial infarction, on the basis of high-intensity statin therapy, subcutaneous injection of aliciclizumab every two weeks compared with placebo, after 52 weeks, the average change in the percentage of non-infarction-associated atherosclerotic plaque volume decreased significantly, and the coronary plaque of non-infarction-associated arteries resolved significantly, but further research is needed to understand whether aliciclimumab can improve clinical outcomes in this group.
Target PCSK9
PCSK9 is a secretory serine protease synthesized by the liver that binds to and degrades LDL receptors, thereby reducing the clearance of serum LDL-C by LDL receptors.
PCSK9 inhibitors are a research hotspot in the field of blood lipids in recent years. By inhibiting PCSK9, LDL receptor degradation can be blocked and LDL-C clearance can be promoted.
At present, PCSK9 inhibitors (iloclizumab, aliciclimab) that are increasingly widely used in clinical practice are monoclonal antibodies, thereby inhibiting PCSK9 activity and thus exerting a powerful cholesterol-lowering effect.
Not only that, the FOLIER study that ended in 2017 and the ODYSSEY-CV outcomes study published the following year confirmed that the application of PCSK9 inhibitors on the basis of statin treatment has a more powerful cholesterol-lowering effect and a more significant effect on reducing ASCVD events, laying a solid foundation for its widespread clinical application.
In addition to monoclonal antibody PCSK9 inhibitors, several innovative drug studies aim to reduce LDL-C levels by influencing PSCK9 function or expression.
In terms of inhibiting the function of PCSK9, clinical trials based on small molecule drugs, peptide mimetics, antibody-like drugs (adnectin) and even vaccines are actively underway.
In terms of interfering with PCSK9 expression, clinical trials based on antisense oligonucleotide drugs (ASOs), small interfering ribonucleic acid (siRNA) therapies, and even CRISPR gene editing technology (the main editing targets in the current study are PCSK9 and ANGPTL3) are also being explored.
It is worth mentioning that one of the small interference ribonucleic acid (siRNA) - Inclisiran, because of its ease of use, only two injections a year; and the cholesterol-lowering effect is strong, two injections a year can reduce cholesterol by more than 50% and more attention.
The results of two previously published Phase 3 clinical studies (ORION series of studies) confirm that the application of Inclisiran therapy can reduce LDL-C by more than 50%. The drug's cholesterol-lowering effects are comparable to PCSK9 inhibitors, and the results are encouraging enough to last for half a year with a single injection.
For patients with atherosclerotic cardiovascular disease or the same risk factors, subcutaneous injection of Inclisiran every 6 months not only reduces patient LDL-C levels by up to 50%, but also significantly reduces levels of non-hdL-cholesterol (HDL-C), apolipoprotein B (ApoB), triglycerides, and lipoprotein (a).
Based on the results of these studies, the drug regulatory authorities in Europe and the United States have approved the use of Inclisiran in specific types of adult patients with hypercholesterolemia and mixed dyslipidemia.
In China, China's first Inclisiran injection was completed in Boao, Hainan province in July 2021.
The fly in the ointment is that there have been no randomized clinical trials of the drug to date for clinical endpoints.
Based on the relatively long duration of action of the siRNA drug Inclisiran and the relatively convenient mode of administration, the efficacy of the siRNA drug in patients with different characteristics is also being explored.
EHJ Blockbuster Review New Era of Lipid Reduction!
Earlier this year, the European Heart Journal (EHJ) published a blockbuster review. The paper points out that the current drug development and treatment concept of lipid-lowering therapy is undergoing great changes!
Screenshot source: European Heart Journal
As the cornerstone of lipid management, statins have always played a fairly important role in the treatment of atherosclerotic disease.
With the continuous advent of innovative drugs with administered dosage forms and different targets of action, the whole process of blood lipid management for patients with cardiovascular diseases in the future is expected to be more convenient and efficient! Innovative drugs and innovative therapies for other dyslipidemia pathway treatment targets will also bring hope for more reasonable and better control of the occurrence and development of atherosclerosis.
Lipid-lowering therapy, the future can be expected!