Intensive Lipid-lowering Therapy Research Articles

Impact of Intensive Lipid Lowering Therapy With Evolocumab on Plaque Phenotype Changes in Acute Coronary Syndrome Patients With Elevated Lp(a) Levels: A HUYGENS Sub Study

Impact of Intensive Lipid Lowering Therapy With Evolocumab on Plaque Phenotype Changes in Acute Coronary Syndrome Patients With Elevated Lp(a) Levels: A HUYGENS Sub Study

Low Remnant Cholesterol and In-Hospital Bleeding Risk After Ischemic Stroke or Transient Ischemic Attack.

Bleeding risk brought by intensive lipid-lowering therapy and low low-density lipoprotein cholesterol is concerning, while evidence regarding the relationship between remnant cholesterol and bleeding is frightening. This study aimed to investigate the association between remnant cholesterol at admission and an in-hospital bleeding event after acute ischemic stroke or transient ischemic attack (TIA). A total of 3222 eligible patients admitted to Shanghai Huashan Hospital between 2015 and 2021 with complete lipid data were analyzed. Patients were classified into low (<20.0 mg/dL), moderate (20.0-29.9 mg/dL), and high (≥30 mg/dL) groups by remnant cholesterol. The mean age of patients was 63.0± 13.1 years, including 2301 (71.4%) men and 651 (20.2%) with TIA. The median (interquartile range) of remnant cholesterol was 18.6 (13.5-25.9) mg/dL. After adjustment for confounding variables, patients with low remnant cholesterol had a higher risk of bleeding events (odds ratio, 2.56 [95% CI, 1.12-6.67]) than those with moderate remnant cholesterol. The high remnant cholesterol group was not significantly associated with bleeding risk. Combined assessment of low-density lipoprotein cholesterol and remnant cholesterol further identified patients with the highest risk of bleeding events. Low remnant cholesterol levels were associated with bleeding events during the acute stage of ischemic stroke and TIA. The assessment of remnant cholesterol could inform the bleeding risk during hospitalization both for patients and physicians in clinical practice.

Efficacy of Alirocumab, Evolocumab, and Inclisiran in Patients with Hypercholesterolemia at Increased Cardiovascular Risk.

Background and Objectives: Lowering low-density lipoprotein (LDL-C) levels is critical for preventing atherosclerotic cardiovascular disease, yet some patients fail to reach the LDL-C targets despite available intensive lipid-lowering therapies. This study assessed the effectiveness and safety profile of alirocumab, evolocumab, and inclisiran in lipid reduction. Materials and Methods: A cohort of 51 patients (median (Q1-Q3) age: 49.0 (39.5-57.5) years) was analyzed. Eligibility included an LDL-C level > 2.5 mmol/L while on the maximum tolerated dose of statin and ezetimibe, a diagnosis of familial hypercholesterolemia, or a very high risk of cardiovascular diseases following myocardial infarction within 12 months prior to the study. Follow-ups and lab assessments were conducted at baseline (51 patients), 3 months (51 patients), and 15 months (26 patients) after the treatment initiation. Results: Median initial LDL-C levels 4.1 (2.9-5.0) mmol/L, decreasing significantly to 1.1 (0.9-1.6) mmol/L at 3 months and 1.0 (0.7-1.8) mmol/L at 15 months (p < 0.001). Total cholesterol also reduced significantly compared to baseline at both intervals (p < 0.001). No substantial differences in LDL-C or total cholesterol levels were observed between 3- and 15-month observations (p > 0.05). No statistically significant differences were noted in cholesterol reduction among the alirocumab, evolocumab, and inclisiran groups at 3 months. The safety profile was favorable, with no reported adverse cardiovascular events or significant changes in alanine transaminase, creatinine, or creatine kinase levels. Conclusions: Alirocumab, evolocumab, and inclisiran notably decreased LDL-C and total cholesterol levels without significant adverse effects, underscoring their potential as effective treatments in patients who do not achieve lipid targets with conventional therapies.

Efficacy and safety of bempedoic acid in acute coronary syndrome. Design of the clinical trial ES-BempeDACS

Introduction and objectivesOnly about 1 out of every 3 patients with acute myocardial infarction (AMI) achieve low-density lipoprotein cholesterol (LDL-C) values <55mg/dL in the first year. The present study aims to evaluate the impact of early intensive therapy on lipid control after an AMI. MethodsAn independent, prospective, pragmatic, controlled, randomized, open-label, evaluator-blinded clinical trial (PROBE design) will analyze the efficacy and safety of an oral lipid-lowering triple therapy: high-potency statin+bempedoic acid (BA) 180mg+ezetimibe (EZ) 10mg versus current European-based guidelines (high-potency statin±EZ 10mg), in AMI patients. LDL-C will be determined within the first 48hours. Patients with LDL-C ≥ 115mg/dL (without previous statin therapy), ≥ 100mg/dL (with previous low-potency or high-potency statin therapy at submaximal dose), or ≥ 70mg/dL (with previous high-potency statin therapy at high dose) will be randomly assigned 1:1 between 24 and 72hours post-AMI to the BA/EZ combination or to statin±EZ, without BA. The primary endpoint is the proportion of patients reaching LDL-C <55mg/dL at 8 weeks after treatment. ResultsThe results of this study will provide novel information for post-AMI LDL-C control by evaluating the usefulness of an early intensive lipid-lowering strategy based on triple oral therapy. ConclusionsEarly intensive lipid-lowering triple oral therapy vs the treatment recommended by current clinical practice guidelines could facilitate the achievement of optimal LDL-C levels in the first 2 months after AMI (a high-risk period). Identification numberEudraCT 2021-006550-31.

Strike early-strike strong lipid-lowering strategy with PCSK9i in ACS patients. Real-world evidence from AT-TARGET-IT registry.

No data are available on early initiation of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) in patients with acute coronary syndrome (ACS) in real-world. This study investigates the effects of PCSK9i started at time of ACS hospitalization on lipid control and major CV events in real-world. The lipid control outcome was the percentage of patients reaching the LDL-C target of < 55 mg/dL at first lipid control. The clinical outcome was the incidence of composite major CV events (all cause death, non-fatal MI, non-fatal stroke, and ischemia-driven revascularization) during follow-up in relation to quartiles of LDL-C at first lipid control. We included 771 patients with ACS from AT-TARGET-IT registry, receiving PCSK9i prescription during hospitalization or at discharge. Median LDL-C was 137 mg/dL and decreased to 43 mg/dL at first lipid control. 527 (68.3%) patients achieved LDL-C target at the first lipid control at a median time of 37 days from hospitalization; of them, 404 (76.8%) were discharged on statin plus ezetimibe background therapy. Event curves through a median follow-up of 11 months across quartiles of LDL-C showed a stepwise lower risk of 4P-MACE, 3P-MACE, all-cause mortality, and ischemia-driven revascularization in lower quartile of LDL-C values at first lipid control (<23 mg/dL) and in patients reaching LDL-C <55 mg/dL. Intensive and early lipid-lowering therapy using PCSK9i in patients with ACS (strike early strike strong strategy) is safe and effective in clinical practice and associated with a reduction of residual CV risk.

Abstract 1028: Cytotoxic CD4+ T Cells: Unraveling The Residual Risk In Lipid Lowering For Type 2 Diabetes Patients

Type 2 Diabetes (T2D) significantly increases the risk of cardiovascular diseases (CVDs), marked by severe plaque pathology resistant to standard cholesterol-lowering treatments. While the roles of the innate immune system and macrophages in CVDs are well-established, T cell alterations, particularly involving cytotoxic CD4 T cells (CD4 CTLs), remain unexplored in human atherosclerotic plaques. In our study, we aimed to identify the phenotype and function of CD4 CTLs in blood &amp; plaque tissue, in the context of T2D. Using unbiased single-cell RNA sequencing (scRNA-seq) analysis, we examined over 70,000 immune cells from 22 plaques of patients undergoing carotid endarterectomy (T2D: n=12, Non-Diabetic (ND): n=10), &amp; peripheral blood mononuclear cells (PBMCs) from the CHORD study (NCT04369664) (T2D: n=12, ND: n=4). scRNA-seq analysis revealed a diverse population of CD4 T cells, like naïve, central memory (CM), effector memory (EM), tissue resident memory (Trm), T regulatory (Tregs), &amp; two clusters of cytotoxic (CTL) T cells expressing canonical cytotoxicity-related genes. Cluster 5 expressed GZMB, GNLY, PRF1 , whereas Cluster 10 expressed GZMA, GZMK . Cell-cell communication analysis demonstrated that both CTL clusters received signaling from dendritic cells and macrophages, including TREM2+ macrophages. CTL T cells reciprocally communicated with clusters of EM and EMRA CD8 T cells, underscoring their central role in plaque cell-cell communication. Notably, Cluster 5, one of these two CTL clusters, was expanded in T2D plaque samples (p=0.032) and expressed genes involved in chemotaxis, IL-2 signaling, &amp; transcription factors (e.g., RUNX3, TBX21 ) involved in T cell activation. The equivalent of CD4 CTL phenotype was found to be expanded in T2D individuals compared to controls, &amp; these elevated levels persisted in T2D patients following intensive lipid-lowering therapy, indicating resistance to the treatment regimen. In summary, our study emphasizes the crucial role of CD4 CTLs in the immune dynamics of atherosclerotic plaques. The observed resistance of CTLs to lipid-lowering interventions underscores the necessity for targeted therapeutic strategies to address the distinctive immune changes in T2D-associated cardiovascular diseases.

Eficacia y seguridad del ácido bempedoico en el síndrome coronario agudo. Diseño del ensayo clínico ES-BempeDACS

Introduction and objectivesOnly about 1 out of every 3 patients with acute myocardial infarction (AMI) achieve low-density lipoprotein cholesterol (LDL-C) values <55mg/dL in the first year. The present study aims to evaluate the impact of early intensive therapy on lipid control after an AMI. MethodsAn independent, prospective, pragmatic, controlled, randomized, open-label, evaluator-blinded clinical trial (PROBE design) will analyze the efficacy and safety of an oral lipid-lowering triple therapy: high-potency statin+bempedoic acid (BA) 180mg+ezetimibe (EZ) 10mg versus current European-based guidelines (high-potency statin±EZ 10mg), in AMI patients. LDL-C will be determined within the first 48hours. Patients with LDL-C ≥ 115mg/dL (without previous statin therapy), ≥ 100mg/dL (with previous low-potency or high-potency statin therapy at submaximal dose), or ≥ 70mg/dL (with previous high-potency statin therapy at high dose) will be randomly assigned 1:1 between 24 and 72hours post-AMI to the BA/EZ combination or to statin±EZ, without BA. The primary endpoint is the proportion of patients reaching LDL-C <55mg/dL at 8 weeks after treatment. ResultsThe results of this study will provide novel information for post-AMI LDL-C control by evaluating the usefulness of an early intensive lipid-lowering strategy based on triple oral therapy. ConclusionsEarly intensive lipid-lowering triple oral therapy vs the treatment recommended by current clinical practice guidelines could facilitate the achievement of optimal LDL-C levels in the first 2 months after AMI (a high-risk period). Identification numberEudraCT 2021-006550-31.

Lipid-Lowering Therapy after Acute Coronary Syndrome.

Achieving guideline-recommended low-density lipoprotein cholesterol (LDL-C) targets remains a significant challenge in clinical practice. This review assesses the barriers to reaching LDL-C goals and explores the potential solutions to these issues. When aiming for the recommended LDL-C goal, strategies like "lower is better" and "strike early and strong" should be used. The evidence supports the safety and efficacy of intensive lipid-lowering therapy post-acute coronary syndrome (ACS), leading to improved long-term cardiovascular health and atherosclerotic plaque stabilization. Despite the availability of effective lipid-lowering therapies, such as high-intensity statins, ezetimibe, the combination of both, bempedoic acid, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, a substantial proportion of patients do not meet their LDL-C targets. Contributing factors include systemic healthcare barriers, healthcare provider inertia, patient non-adherence, and statin intolerance. Statin intolerance, often rather statin reluctance, is a notable obstacle due to perceived or expected side effects, which can lead to discontinuation of therapy. In conclusion, while there are obstacles to achieving optimal LDL-C levels post-ACS, these can be overcome with a combination of patient-centric approaches, clinical vigilance, and the judicious use of available therapies. The safety and necessity of reaching lower LDL-C goals to improve outcomes in patients post-ACS are well-supported by current evidence.

Cholesterol-Lowering Strategies for Cardiovascular Disease Prevention: The Importance of Intensive Treatment and the Simplification of Medical Therapy.

Cardiovascular diseases (CVDs) are a leading global cause of mortality and are primarily driven by atherosclerotic coronary artery disease. Their pathogenesis involves multi-factorial mechanisms, among which low-density lipoprotein (LDL) plays a causative role. Recent ESC/EAS guidelines advocate for a shift toward new risk estimation algorithms that better emphasize non-fatal cardiovascular events, lifetime risk prediction, and tailored pharmacological approaches, including statin + ezetimibe and triple therapy, in specific cases. Intensive lipid-lowering therapy has been shown to be pivotal, especially in post-acute coronary events. Intracoronary imaging has revealed insights into the composition of plaque and demonstrated the significant regression that can be achieved through the use of statins such as rosuvastatin and atorvastatin. The positive effects of Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors, particularly alirocumab and evolocumab, on plaque regression, have been demonstrated. Inclisiran, which targets PCSK9 gene expression, significantly reduces LDL cholesterol. The associated challenges include hesitancy to prescribe intensive regimens and limited treatment adherence, highlighting the need for pharmacological combinations to improve therapeutic outcomes.

The importance of LDL-C lowering in atherosclerotic cardiovascular disease prevention: Lower for longer is better

Cumulative exposure to low-density lipoprotein cholesterol (LDL-C) is a key driver of atherosclerotic cardiovascular disease (ASCVD) risk. An armamentarium of therapies to achieve robust and sustained reduction in LDL-C can reduce ASCVD risk. The gold standard for LDL-C assessment is ultracentrifugation but in routine clinical practice LDL-C is usually calculated and the most accurate calculation is the Martin/Hopkins equation. For primary prevention, consideration of estimated ASCVD risk frames decision making regarding use of statins and other therapies, and tools such as risk enhancing factors and coronary artery calcium enable tailoring of risk assessment and decision making. In patients with diabetes, lipid lowering therapy is recommended in most patients to reduce ASCVD risk with an opportunity to tailor therapy based on other risk factors. Patients with primary hypercholesterolemia and familial hypercholesterolemia (FH) with baseline LDL-C greater than or equal to 190 mg/dL are at elevated risk, and LDL-C lowering with high-intensity statin therapy is often combined with non-statin therapies to prevent ASCVD. Secondary prevention of ASCVD, including in patients with prior myocardial infarction or stroke, requires intensive lipid lowering therapy and lifestyle modification approaches. There is no established LDL-C level below which benefit ceases or safety concerns arise. When further LDL-C lowering is required beyond lifestyle modifications and statin therapy, additional medications include oral ezetimibe and bempedoic acid, or injectables such as PCSK9 monoclonal antibodies or siRNA therapy. A novel agent that acts independently of hepatic LDL receptors is evinacumab, which is approved for patients with homozygous FH. Other emerging agents are targeted at Lp(a) and CETP. In light of the expanding lipid treatment landscape, this manuscript reviews the importance of early, intensive, and sustained LDL-C-lowering for primary and secondary prevention of ASCVD.

Delipid extracorporeal lipoprotein filter from plasma system: a new intensive lipid lowering therapy for patients with acute ischemic stroke.

To investigate the safety and efficacy of the delipid extracorporeal lipoprotein filter from plasma (DELP) system, a new low-density lipoprotein cholesterol (LDL-C) adsorption system, in acute ischemic stroke (AIS) patients. In the present study, a total of 180 AIS patients were enrolled during March 2019 to February 2021. They were divided into DELP group (n1 = 90) and the control group (n2 = 90). The treatment protocol and vascular access of DELP treatment was established and evaluated. For the DELP group, clinical data and laboratory results including plasma lipid and safety parameters before and after the apheresis were collected and analyzed. For all participants, neurological scores were assessed and recorded. For the DELP group, 90 patients including 70 males and 20 females were included. The mean LDL-C was significantly decreased from 3.15 ± 0.80 mmol/L to 2.18 ± 0.63 mmol/L (30.79%, p < 0.001) during a single DELP treatment, and decreased from 3.42 ± 0.87 mmol/L to 1.87 ± 0.48 mmol/L (45.32%, p < 0.001) after two DELP treatments. No clinically relevant changes were observed in hematologic safety parameters and blood pressure levels except for hematocrit and total protein throughout the whole period of DELP treatment. The DELP group showed improvement relative to the control group in National Institute of Health stroke scale scores (NIHSS) on the 14th and 90th day after stroke. Moreover, the DELP group had a significantly higher ratio of mRS 0 to 1 on the 90th day after stroke. The new LDL-C adsorption system, the DELP system, may provide a new option for intensive lipid lowering therapy in AIS patients in view of its safety, efficacy, and operation feasibility.

Efficacy of paclitaxel-coated balloon angioplasty combined with intensive lipid-lowering therapy for ST-segment elevation myocardial infarction: insights from near-infrared spectroscopy.

Efficacy of paclitaxel-coated balloon angioplasty combined with intensive lipid-lowering therapy for ST-segment elevation myocardial infarction: insights from near-infrared spectroscopy.

Abstract TP257: Atherogenic Dyslipidemia Advances Crucially the Aortic Complicated Lesion in Cryptogenic Stroke

Background and purpose: The aortic complicated lesion (ACL) is a notable embolic source of cryptogenic stroke (CS) observed in 10-60 % of patients. Although the antithrombotic and statin therapy are certainly effective, the recurrence of aortogenic stroke is not rare. Atherogenic dyslipidemia (AD) is regarded as the significant residual risk of cardiovascular diseases even under the statin remedy and characterized by low high-density lipoprotein (HDL) and high triglyceride (TG). In the present study, we aimed to clarify the underlying association between ACL and AD. Methods: Clinical data of CS patients admitted between April 2014 and December 2016 in Japanese 8 institutes and underwent transesophageal echocardiography (TEE) were analyzed in the present study. Low HDL was defined as ≤ 40 mg/dl and high TG was defined as ≥ 150 mg/dl in the fasting condition, respectively. Furthermore, AD must satisfy both cut-off values. Based on these criteria, patients were divided into 4 groups as AD group, HDL group, TG group, and non-AD group to compare the clinical features. Results: Of 664 CS patients, 68 (57 men, 68.6 ± 11.1 years) met the criteria of AD (AD group), and 108 (90 men, 68.5 ±13.7 years) fulfilled the low HDL only (HDL group), 115 (76 men, 66.9 ± 11.7 years) merely met the high TG (TG group), 373 (223 men, 69.4 ± 13.1 years) satisfied the neither (non-AD group). In a univariate analysis, ACL in arch revealed with TEE was significantly more frequent in AD group (55.9 vs 38.0 vs 39.1 vs 33.8 %, p=0.007). In a multiple regression analysis, male (OR 2.57, 95%CI 1.23-5.38, p=0.012), body mass index (unit OR 1.16, 95%CI 1.08-1.25, p&lt;0.001), diabetes (OR 2.52, 95%CI 1.41-4.53, p=0.002), ACL in arch (OR 2.12, 95%CI 1.19-3.80, p=0.011) were independently, and past history of stroke (OR 0.35, 95%CI 0.14-0.90, p=0.030) was inversely associated with AD group. Conclusions: Although the previous study exhibited that AD was predominantly associated with intracranial stenosis in atherothrombotic brain infarction, AD was also crucially related to ACL in CS in the present study. Concerning the aortogenic stroke, more intensive and pleiotropic lipid-lowering therapy would be efficacious for further treatment.

Lipid assessment and achievement of secondary prevention european society of cardiology guideline targets in patients with atherosclerotic cardiovascular disease with and without depression

Abstract Background Patients who have a diagnosis of atherosclerotic cardiovascular disease (aCVD) who also have depression (Dep) have a worse CV prognosis than those without Dep. Appropriate secondary prevention greatly improves CVD outcomes. The European Society of Cardiology (ESC) provide guideline targets for lipid levels (2016 &amp; 2019). It is unknown how well these targets are achieved and maintained over time in patients with aCVD at a population level and whether this differs in those with and without Dep. Purpose To investigate the assessment of lipid levels and/or achievement of guideline targets in patients with aCVD with and without Dep over an 11-year period. Methods A retrospective observational cohort study of patients with aCVD was conducted on individual-level linked electronic health record data between 2009 &amp;2019 using the all-Wales SAIL databank. Clinical codes were used to identify aCVD and Dep diagnoses, lipid assessments and lipid-lowering therapy (LLT) from GP data. The proportions of those having lipid assessments during each calendar year, lipid levels achieving ESC 2016 guideline targets and current LLT were documented. Results In 2009, the aCVD cohort comprised of 183,275 patients (44% female) with a mean age (70.6 ±12.3 years), of whom 22% had a Dep diagnosis (56.6% female). In 2009, lipid levels were assessed in 63.1% of patients, dropping to 48.3% by 2019 (68.06% Dep, 61.65% non-Dep in 2009 and 51.7% Dep, 46.84% non-Dep in 2019. Table and Figure). Over the period of study an increasing proportion of patients were prescribed High intensity statins (HIS) and a decreasing proportion were prescribed low intensity statin (LIS) and/or Ezetimibe. Dep patients were more likely to be treated with HIS and/or Ezetimibe and less likely to receive LIS throughout compared with non-Dep (table). An increasing trend for lipid targets being achieved was observed between 2009 and 2019 in those being tested (Table and Figure). However, a significantly smaller proportion of those with Dep met the ESC targets vs non-Dep over the period of study (Table and Figure). Conclusion The proportion of aCVD patients having their lipids checked fell progressively between 2009 and 2019, although a greater proportion of those "checked" patients had achieved LDL-C and non-HDL-C targets, although the proportion who met these targets remained low. Despite patients with aCVD and Dep being more likely to have their lipids assessed and to be prescribed more intensive LLT those without Dep, with the "gap" widening over time. Considerable additional effort will be required in the future to meet the more intensive 2019 targets in these very high risk patients.

Almost 1 in 2 patients with acute coronary syndrome are extremely high-risk and potential candidates for in-hospital triple lipid-lowering therapy: data from the CALLINICUS-Hellas Registry

Abstract Introduction The great heterogeneity of acute coronary syndrome (ACS) patients in the risk for cardiovascular events recurrence, prompted a recent position paper endorsed by the International Lipid Expert Panel to propose criteria, i.e. coexistence of multivessel coronary artery disease (CAD), polyvascular disease, heterozygous familial hypercholesterolemia (heFH), diabetes mellitus (DM) with estimated glomerular filtration rate (eGFR) &amp;lt;60 ml/min/1.73 m2 and/or lipoprotein (a) [Lp(a)] &amp;gt;50 mg/dL etc., which define the extremely high-risk ACS patients for whom an low-density lipoprotein cholesterol (LDL-C) &amp;lt;40 mg/dL was proposed. Purpose To estimate the proportion of patients with ACS that fulfill the criteria of the extremely high-risk group and are potential candidates for "extremely" intensive early lipid-lowering therapy (LLT) aiming at an LDL-C &amp;lt;40 mg/dL. Methods We recruited 780 consecutive patients with ACS who were participants of the CALLINICUS-Hellas Registry which is a prospective multicenter observational study that explores the adherence to LLT, the achievement of LDL-C targets and the cardiovascular events at 6- and 24-months after hospital discharge of patients with ACS. Results The prevalence of high risk components was: heFH 13.5%, multivessel CAD 44%, polyvascular disease 3.2%,and DM with eGFR &amp;lt;60 ml/min/1.73 m2 and/or Lp(a) &amp;gt;50 mg/dL 8.1%. By excluding the overlapping between these conditions, 430 ACS patients (55.1%) had at least one of the characteristics which define the extremely high-risk patients (Figure). Presuming a 65% LDL-C reduction of the levels (the pretreatment if on LLT prior admission or the admission if not on prior LLT) of the extremely high-risk ACS patients by taking a maximum dual LLT (intense statin plus ezetimibe), 312 patients, i.e., 40% of all initially recruited patients would fail to achieve an LDL-C &amp;lt;40 mg/dL suggesting that they require additional LLT, namely, a proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i). Conclusions Almost 1 in 2 patients with ACS have extremely high-risk characteristics and are candidates for in-hospital triple LLT (statin plus ezetimibe plus PCSK9i) aiming at an LDL-C &amp;lt;40 mg/dL, a strategy shown to improve plaque stability and possibly to reduce the recurrence rate of early coronary events.Figure

Reduction in the risk of major adverse limb events with ezetimibe versus placebo in addition to statin therapy: insights from the IMPROVE IT trial

Abstract Background/Introduction Patients with peripheral artery disease (PAD) are at risk of developing progressive symptoms leading to revascularization as well as major adverse limb events such as critical limb ischemia and amputation. Recently, two trials of PCSK9 inhibitors, which lower both LDL-C and Lp(a) have demonstrated reductions in MALE and peripheral revascularization. Whether this benefit is present for other LDL-C lowering therapies has not been well described. Purpose To evaluate whether LDL-C lowering with ezetimibe reduces the risk of adverse limb events. Methods IMPROVE-IT randomized 18,144 patients with acute coronary syndrome (ACS), including 1,005 with PAD, to ezetimibe or placebo on top of statin and followed for a median of 6 years. Two vascular specialists blinded to treatment allocation independently reviewed all adverse events to categorize limb outcomes including critical limb ischemia (CLI), and related amputation as well as progressive symptoms leading to lower extremity revascularization (worsening PAD). Total limb outcomes over follow up were compared by treatment groups using negative binomial regression and relative risks (RR) are presented. Results A total of 397 patients had worsening symptoms (in 346 PAD patients) and 43 developed CLI (in 36 patients) during follow up. The risk of total PAD events (CLI or worsening symptoms) was lower with ezetimibe versus placebo (RR 0.77, 95% CI 0.62 – 0.96, p=0.018) with a consistent trend for both components (Figure Panel A). When evaluating the relationship of achieved LDL-C at 1-month post-randomization and the risk of first PAD event, there appeared to a linear relationship extending to an LDL-C less than 25 mg/dL (Figure Panel B). Conclusion Further lowering of LDL-C with ezetimibe on top of statin therapy in patients with ACS was associated with a lower risk of adverse limb events over long-term follow up including CLI and progressive disease leading to revascularization. These data support the importance of intensive lipid lowering therapies in improving limb outcomes in patients with atherosclerotic vascular disease. In addition, these data support LDL-C as a treatment target for optimizing outcomes in patients with peripheral artery disease.Figure Panel AFigure Panel B

Rationale and design of a randomized controlled trial: The effect of intensive lipid-lowering therapy with PCSK9 inhibitor on endothelial-coverage of stent strut after percutaneous coronary intervention (PCI) for patients with acute coronary syndrome (ACS): Optical coherence tomography (OCT) study (PIECES-OCT study)

BackgroundFor the patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI), dual antiplatelet therapy (DAPT) for at least 1 year is recommended in the guidelines to minimize the risk of stent thrombosis. Persistently uncovered stent strut means delayed neointima formation and extend the window of time in which the stent is prone to thrombosis. Previous studies showed that statins could improve post-stenting strut endothelial coverage for patients undergoing PCI. However, there are lack of evidences on whether early initiation of proprotein convertase subtilisin/Kexin type 9 monoclonal antibody (PCSK9mAb) after PCI in ACS patients can further improve the rate of stent strut coverage on the background of oral lipid-lowering therapy (LLT). MethodsThis is a single-center, randomized trial to enroll 36 patients undergoing PCI with a clinical diagnosis of non-ST-segment elevation ACS. The baseline level of low-density lipoprotein cholesterol (LDL-C) of these patients are between 1.4 mmol/L and 3.4 mmol/L. Patients will be assigned to intensive lipid-lowering therapy (LLT) with PCSK9mAb group and conventional LLT without PCSK9mAb group for 12 weeks in a clinical follow-up setting according to 1: 1 randomization. the rate of stent strut endothelial coverage by optical coherence tomography (OCT) examination at 12 weeks after enrollment between the groups will be compared. ConclusionThis will be the first study to investigate changes in the rate of stent strut endothelial coverage under intensive LLT with PCSK9mAb by OCT examination in ACS patients undergoing PCI. The finding of this study will provide clinical evidence for future research about the hypothesis of a novel strategy of “intensive LLT (PCSK9mAb + statin ± ezetimibe) combined with shortened DAPT duration” for ACS patients undergoing PCI.Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: ChiCTR2200063395.

Inclisiran in patients with prior myocardial infarction: A post hoc pooled analysis of the ORION-10 and ORION-11 Phase 3 randomised trials

Background and aimsAmong patients with prior myocardial infarction (MI), the risk of future ischaemic cardiovascular events is increased, and intensive lipid-lowering therapy (LLT) is indicated to achieve guideline-recommended low-density lipoprotein cholesterol (LDL-C) goals. Here, the efficacy and safety of inclisiran, a small interfering ribonucleic acid, were evaluated in patients with or without prior MI from the pooled ORION-10 and ORION-11 Phase 3 trials. MethodsPatients (n = 2636) were randomised 1:1 to receive 284 mg inclisiran (300 mg inclisiran sodium) or placebo on Day 1, Day 90, and 6-monthly thereafter over 18 months, along with background oral LLT, including statins. Of these, 1643 (62.3%) patients had an MI prior to randomisation, stratified as recent (>3 months to <1 year) or remote (≥1 year), and 993 (37.7%) patients were without a prior MI. The percentage change in LDL-C from baseline and safety were assessed. ResultsBaseline characteristics were well balanced across the treatment arms and MI strata. The mean (95% confidence interval) placebo-corrected LDL-C reductions from baseline to Day 510 with inclisiran were 52.6% (40.1, 65.1), 50.4% (47.0, 53.8), and 51.6% (47.4, 55.9) for recent, remote, and no prior MI, respectively. Corresponding time-adjusted LDL-C reductions were 50.0% (41.4, 58.7), 52.2% (49.8, 54.7), and 51.2% (48.1, 54.2). In each MI stratum, treatment-emergent adverse events (TEAEs) at the injection site (all mild to moderate) were observed more in inclisiran-treated patients than placebo, without an excess of other TEAEs. ConclusionsInclisiran provided effective and consistent LDL-C lowering, irrespective of MI status.

Effect of Intensive Lipid-Lowering Therapy on Coronary Plaque Stabilization Derived from Optical Coherence Tomography: a Meta-analysis and Meta-regression.

The definitive impacts of intensive lipid-lowering therapy (LLT) on plaque stabilization and the relationship between the key markers during LLT and plaque stability remain unquestioned. Thus, these meta-analysis and meta-regression intend to holistically evaluate the influence exerted by rigorous LLT on the minimum fibrous cap thickness (FCT) and maximum lipid arc as discerned through optical coherence tomography (OCT). This study further scrutinizes the correlation of this impact with variations in high-sensitivity C-reactive protein (hs-CRP), low-density lipoprotein cholesterol (LDL-C), or additional parameters within patients diagnosed with coronary artery disease (CAD). Comprehensive searches were conducted on platforms including PubMed, Embase, and the Cochrane Library for randomized controlled trials (RCTs) published until June 1, 2023. The search was language agnostic and targeted RCTs elaborating on the correlation between high-intensity statin therapy or statins used concomitantly with other lipid-lowering medications and the minimum FCT and maximum lipid arc as assessed by OCT. The meta-analyses were executed employing a standard mean difference (SMD) algorithm with random-effects on continuous variables. These methodologies align with the Preferred Reporting Items for Systematic and Meta-analysis (PRISMA) guidelines. A spectrum of 12 RCTs engaging 972 patients were identified and mobilized for these analyses. Meta-analysis outcomes depicted a conspicuous correlation between intensive LLT and an enhanced minimum FCT (12 studies with 972 participants; SMD, 0.87; 95% CI, 0.54 to 1.21; P < 0.01), reduced maximum lipid arc (9 studies with 564 participants; SMD, -0.43; 95% CI, -0.58 to -0.29; P < 0.01). Meta-regression analysis has determined an association of elevated minimum FCT with decreased LDL-C (β, -0.0157; 95% CI, -0.0292 to -0.0023; P = 0.025), total cholesterol (TC) (β, -0.0154; 95% CI, -0.0303 to -0.0005; P = 0.044), and apolipoprotein B (ApoB) (β, -0.0209; 95% CI, -0.0361 to -0.0057; P = 0.022). However, no significant association was discerned relative to variations in hs-CRP/CRP (β, -0.1518; 95% CI, -1.3766 to -1.0730; P = 0.772), triglyceride (TG) (β, -0.0030; 95% CI, -0.0258 to -0.0318; P = 0.822), and high-density lipoprotein cholesterol (HDL-C) (β, 0.0313; 95% CI, -0.0965 to 0.1590; P = 0.608). Subsequent subgroup meta-analysis demonstrated that high-intensity statin therapy (5 studies with 204 participants; SMD, 1.03; 95% CI, 0.67 to 1.39; P < 0.01), as well as a combinative approach including PCSK9 antibodies and statins (3 studies with 522 participants; SMD, 1.17; 95% CI, 0.62 to 1.73; P < 0.01) contributed to an increase in minimum FCT. Parallelly, high-intensity statin therapy (4 studies with 183 participants; SMD, -0.42; 95% CI, -0.65 to -0.19; P < 0.01) or the combined application of PCSK9 antibodies and statins (2 studies with 222 participants; SMD, -0.98; 95% CI, -1.26 to -0.70; P < 0.01) was evidenced to decrease the maximum lipid arc. Intensive LLT, mainly high-intensity statin therapy and combined PCSK9 antibody with statin, has a beneficial effect on coronary plaque stabilization derived from OCT in patients with CAD. Coronary plaque stabilization is primarily due to lipid-lowering effect, not anti-inflammatory effect. Moreover, the lipid-lowering effect has nothing to do with the changes in HDL-C and TG, but is mainly related to the reduction of LDL-C, TC, and ApoB.

Intensive Lipid-Lowering Therapy as per the Latest Dyslipidemia Management Guideline in Predicting Favorable Long-Term Clinical Outcomes in Patients Undergoing Coronary Artery Bypass Grafting: A Retrospective Cohort Study.

Background There are limited data on low-density lipoprotein cholesterol (LDL-C) goal achievement per the 2019 European Society of Cardiology/European Atherosclerosis Society dyslipidemia management guidelines and its impact on long-term outcomes in patients undergoing coronary artery bypass grafting (CABG). We investigated the association between LDL-C levels attained 1 year after CABG and the long-term outcomes. Methods and Results A total of 2072 patients diagnosed with multivessel coronary artery disease and undergoing CABG between 2011 and 2020 were included. Patients were categorized by lipid levels at 1 year after CABG, and the occurrence of major adverse cardiovascular and cerebrovascular events (MACCEs) was evaluated. The goal of LDL-C <1.40 mmol/L was attained in only 310 patients (14.9%). During a mean follow-up of 4.2 years after the index 1-year assessment, 25.0% of the patients experienced MACCEs. Multivariable-adjusted hazard ratios (95% CIs) for MACCEs, cardiac death, nonfatal myocardial infarction, nonfatal stroke, revascularization, and cardiac rehospitalization were 1.94 (1.41-2.67), 2.27 (1.29-3.99), 2.45 (1.55-3.88), 1.17 (0.63-2.21), 2.47 (1.31-4.66), and 1.87 (1.19-2.95), respectively, in patients with LDL-C ≥2.60 mmol/L, compared with patients with LDL-C <1.40 mmol/L. The LDL-C levels at 1-year post-CABG were independently associated with long-term MACCEs. Conclusions This retrospective analysis demonstrates that lipid goals are not attained in the vast majority of patients at 1 year after CABG, which is independently associated with the increased risk of long-term MACCEs. Further prospective, multicenter studies are warranted to validate if intensive lipid management could improve the outcomes of patients undergoing CABG.