Early Use of PCSK9 Inhibitors in the Prognosis of Patients with Acute Coronary Syndrome by Protecting Vascular Endothelial Function.

INTRODUCTION: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) has a protective effect on acute coronary syndrome (ACS). However, most studies have shown that this protective effect is based on a decrease in low-density lipoprotein cholesterol, while other mechanisms remain limited. This study aimed to determine whether PCSK9i can improve the prognosis of ACS patients by protecting endothelial function. METHODS: A total of 113 ACS patients were enrolled and randomly assigned to PCSK9i group (PCSK9i combined with statins) and control group (statins only). Blood lipids and endothelial function indicators were measured and analyzed 6 weeks before and after treatment. The effect of PCSK9i on the expression and secretion of endothelial function indicators in vascular endothelial cells were studied by cell experiments. RESULTS: After 6 weeks of treatment, endothelial function indicators such as nitric oxide (NO), thrombomodulin, intercellular cell adhesion molecule-1, endothelin-1, and flow-mediated vasodilation were significantly improved in PCSK9i group compared with control group. Only the changes of NO and von Willebrand factor were associated with blood lipid levels, whereas the changes of other endothelial function indicators were not significantly associated with blood lipid levels. PCSK9i reduced the incidence of major adverse cardiovascular events in patients with ACS compared to those in the control group. In cell experiments, PCSK9i treatment significantly ameliorated LPS induced endothelial injury in HUVECs. CONCLUSION: PCSK9i can protect vascular endothelial function partly independently of its lipid-lowering effect and ameliorate the prognosis of patients with ACS within 6 weeks. This mechanism may involve heat shock transcription factor 1/heat shock proteins -related signaling pathways. Early use of PCSK9i in patients with ACS should be strongly considered in clinical practice.

Updates on Non-Statin LDL-Lowering Therapy.

PURPOSE OF REVIEW: There is ample evidence of the benefits and safety of low-density lipoprotein (LDL)-lowering therapies in the prevention of atherosclerotic cardiovascular disease. While statins remain the first-line agent for LDL reduction, several new therapies are now available. This narrative review provides an overview of currently available non-statin LDL-lowering agents, specifically mechanisms of action and data on efficacy and safety. It also discusses recommendations on their use in clinical practice. RECENT FINDINGS: Ezetimibe, PCSK9 inhibitors, and bempedoic acid have proven safe and efficacious in reducing cardiovascular events in large randomized controlled trials. Inclisiran is a promising agent that suppresses PCSK9 mRNA translation and is currently under investigation in a large clinical outcomes randomized controlled trial assessing its effect on clinical outcomes. Expert consensus advocates for lower LDL targets in higher risk patients and escalation to or a combination of non-statin therapies as needed to achieve these goals.

Impact of Lowering Low-Density Lipoprotein Cholesterol with Contemporary Lipid-Lowering Medicines on Cognitive Function: A Systematic Review and Meta-Analysis.

PURPOSE: To evaluate the potential association between the lowering of low-density lipoprotein cholesterol (LDL-C) with contemporary lipid-lowering medicines and cognitive function. METHODS: Randomized controlled trials (RCTs) in databases including PubMed, Embase, and the Web of Science and all databases in the Cochrane Library and ClinicalTrials.gov were collected from inception to January 1, 2020. The cognitive function of patients receiving proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, statins and ezetimibe was evaluated using meta-analysis. RESULTS: A total of 2910 studies were obtained from databases and other sources. Thirty-three studies were selected by screening, including 11 studies on alirocumab, 9 studies on evolocumab, 11 studies on statins and 2 studies on ezetimibe. In our study, a total of 128,691 patients with no cognitive impairment were divided into an intervention group (66,330 patients) and a control group (62,361 patients). The data were subjected to a random-effects model or a fixed-effects model for meta-analysis. The contemporary lipid-lowering medicines significantly reduced LDL-C in terms of both percentage (WMD: -45.06%, 95% CI -50.12% to -40.00%, P < 0.001) and absolute value (WMD: -64.01 mg/dL, 95% CI -72.25 to -55.78, P < 0.001). Compared with the control group, patients receiving treatment with contemporary lipid-lowering medicines did not show a significant difference in the rate of neurocognitive disorder (RR: 1.02, 95% CI 0.90 to 1.16, I2 = 0.0%, p = 0.696). Subgroup analysis was performed according to the intervention and LDL-C stratification. The result of this subgroup analysis was consistent with the main findings. Regarding global cognitive performance, no difference in major cognition was found among the pooled data (SMD: 0.02, 95% CI -0.01 to 0.04, P = 0.002), except for psychomotor speed (SMD: 0.09, 95% CI 0.02 to 0.16, P = 0.0024). CONCLUSIONS: Contemporary lipid-lowering medicines were not associated with cognitive impairment in RCTs. A low LDL-C level did not influence the incidence of cognitive disorder or global cognitive performance.

Systematic Review for the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.

BACKGROUND: The 2013 American College of Cardiology/American Heart Association guidelines for the treatment of blood cholesterol found little evidence to support the use of nonstatin lipid-modifying medications to reduce atherosclerotic cardiovascular disease (ASCVD) events. Since publication of these guidelines, multiple randomized controlled trials evaluating nonstatin lipid-modifying medications have been published. METHODS: We performed a systematic review to assess the magnitude of benefit and/or harm from additional lipid-modifying therapies compared with statins alone in individuals with known ASCVD or at high risk of ASCVD. We included data from randomized controlled trials with a sample size of >1 000 patients and designed for follow-up >1 year. We performed a comprehensive literature search and identified 10 randomized controlled trials for intensive review, including trials evaluating ezetimibe, niacin, cholesterol-ester transfer protein inhibitors, and PCSK9 inhibitors. The prespecified primary outcome for this review was a composite of fatal cardiovascular events, nonfatal myocardial infarction, and nonfatal stroke. RESULTS: The cardiovascular benefit of nonstatin lipid-modifying therapies varied significantly according to the class of medication. There was evidence for reduced ASCVD morbidity with ezetimibe and 2 PSCK9 inhibitors. Reduced ASCVD mortality rate was reported for 1 PCSK9 inhibitor. The use of ezetimibe/simvastatin versus simvastatin in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) reduced the primary outcome by 1.8% over 7 years (hazard ratio: 0.90; 95% CI: 0.84-0.96], 7-year number needed to treat: 56). The PSCK9 inhibitor evolocumab in the FOURIER study (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) decreased the primary outcome by 1.5% over 2.2 years (hazard ratio: 0.80; 95% CI: 0.73-0.88; 2.2=year number needed to treat: 67). In ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab), alirocumab reduced the primary outcome by 1.6% over 2.8 years (hazard ratio: 0.86; 95% CI: 0.79-0.93; 2.8-year number needed to treat: 63). For ezetimibe and the PSCK9 inhibitors, rates of musculoskeletal, neurocognitive, gastrointestinal, or other adverse event risks did not differ between the treatment and control groups. For patients at high risk of ASCVD already on background statin therapy, there was minimal evidence for improved ASCVD risk or adverse events with cholesterol-ester transfer protein inhibitors. There was no evidence of benefit for the addition of niacin to statin therapy. Direct comparisons of the results of the 10 randomized controlled trials were limited by significant differences in sample size, duration of follow-up, and reported primary outcomes. CONCLUSIONS: In a systematic review of the evidence for adding nonstatin lipid-modifying therapies to statins to reduce ASCVD risk, we found evidence of benefit for ezetimibe and PCSK9 inhibitors but not for niacin or cholesterol-ester transfer protein inhibitors.

Stabilization of vulnerable carotid plaques with proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, a novel class of monoclonal antibodies, reduce low-density lipoprotein cholesterol levels and improve outcomes of myocardial infarction and stroke. However, the effects of PCSK9 inhibitors on carotid plaques remain unclear. We describe three patients treated with PCSK9 inhibitor alirocumab for progressive carotid stenosis despite lipid-lowering statin therapy. All three patients had vulnerable plaques on magnetic resonance (MR) plaque imaging. After alirocumab treatment initiation, no patients suffered stroke or adverse events, and the stabilization of the carotid plaques was observed on MR plaque imaging.

Triglyceride Levels, Alirocumab Treatment, and Cardiovascular Outcomes After an Acute Coronary Syndrome.

BACKGROUND: It is unknown whether clinical benefit of proprotein convertase subtilisin/kexin type 9 inhibitors is associated with baseline or on-treatment triglyceride concentrations. OBJECTIVES: This study sought to examine relations between triglyceride levels and the effect of alirocumab vs placebo on cardiovascular outcomes using prespecified and post hoc analyses of the ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial. METHODS: Patients with recent acute coronary syndrome (ACS) (n = 18,924) and elevated atherogenic lipoproteins despite optimized statin therapy were randomized to alirocumab 75 to 150 mg or matching placebo every 2 weeks subcutaneously. Major adverse cardiovascular events (MACE) were examined in relation to continuous or dichotomous triglyceride concentrations. RESULTS: Median baseline triglyceride concentration was 129 mg/dL. In both treatment groups, a 10-mg/dL higher baseline concentration was associated with an adjusted MACE HR of 1.008 (95% CI: 1.003-1.013; P < 0.005). Baseline triglycerides ≥150 vs <150 mg/dL were associated with a HR of 1.184 (95% CI: 1.080-1.297; P < 0.005). Versus placebo, alirocumab reduced low-density lipoprotein cholesterol from baseline (average, 54.7%) and reduced MACE (HR: 0.85; 95% CI: 0.78-0.93). At month 4, triglyceride levels were reduced from baseline by median 17.7 mg/dL (P < 0.001) and 0.9 mg/dL (P = NS) with alirocumab and placebo, respectively. A 10-mg/dL decline from baseline in triglycerides was associated with lower subsequent risk of MACE with placebo (HR: 0.988; 95% CI: 0.982-0.995; P < 0.005) but not with alirocumab (HR: 0.999; 95% CI: 0.987-1.010; P = 0.82). CONCLUSIONS: Among patients with recent ACS on optimized statin therapy, baseline triglycerides was associated with cardiovascular risk. However, the reduction in triglycerides with alirocumab did not contribute to its clinical benefit. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402).

Novel Therapeutic Approaches for the Management of Elevated Lipoprotein(a): From Traditional Agents to Future Treatment Options.

Cardiovascular disease is the leading cause of mortality worldwide. Despite the availability of effective low-density lipoprotein cholesterol (LDL-C) lowering agents, an increased cardiovascular risk is still observed in individuals with therapeutic LDL-C levels. One of these cardiovascular risk factors is elevated plasma lipoprotein(a) (Lp(a)) concentration, which maintains chronic inflammation through the increased presence of oxidized phospholipids on its surface. In addition, due to its 90 percent homology with the fibrinolytic proenzyme plasminogen, Lp(a) exhibits atherothrombotic effects. These may also contribute to the increased cardiovascular risk in individuals with high Lp(a) levels that previous epidemiological studies have shown to exist independently of LDL-C and other lipid parameters. In this review, the authors overview the novel therapeutic options to achieve effective Lp(a) lowering treatment, which may help to define tailored personalized medicine and reduce the residual cardiovascular risk in high-risk patients. Agents that increase LDL receptor expression, including statins, proprotein convertase subtilisin kexin type 9 inhibitors, and LDL production inhibitors, are also discussed. Other treatment options, e.g., cholesterolester transfer protein inhibitors, nicotinic acid derivatives, thyroid hormone mimetics, lipoprotein apheresis, as well as apolipoprotein(a) reducing antisense oligonucleotides and small interfering RNAs, are also evaluated.

Long-Term Efficacy of Evolocumab in Patients With or Without Multivessel Coronary Disease.

BACKGROUND: In FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), during a median follow-up of 2.2 years, risk reduction for major adverse cardiovascular event with evolocumab was greater in patients with multivessel disease (MVD). The FOURIER Open-Label Extension (FOURIER-OLE) provides an additional median follow-up of 5 years. OBJECTIVES: The purpose of this study was to assess the long-term benefit of evolocumab in patients with and without MVD. METHODS: FOURIER randomized 27,564 patients to evolocumab vs placebo; 6,635 entered FOURIER-OLE. Patients with coronary artery disease were categorized based on the presence of MVD (≥40% stenosis in ≥2 large vessels). The primary endpoint was cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization; the key secondary endpoint was cardiovascular death, myocardial infarction, or stroke. RESULTS: Of 23,656 patients in FOURIER with coronary artery disease, 25.4% had MVD; 5,887 patients continued into FOURIER-OLE. The risk reduction with initial allocation to evolocumab tended to be greater in patients with MVD than in those without: 23% (HR: 0.77 [95% CI: 0.68-0.87]) vs 11% (HR: 0.89 [95% CI: 0.82-0.96]) for the primary and 31% (HR: 0.69 [95% CI: 0.59-0.81]) vs 15% (HR: 0.85 [95% CI: 0.77-0.94]) for the key secondary endpoints (Pinteraction = 0.062 and Pinteraction = 0.031, respectively). The magnitude of benefit tended to grow during the first several years, reaching 37% to 38% reductions in risk in patients with MVD and 23% to 28% reductions in risk in patients without MVD. CONCLUSIONS: Evolocumab reduced the rate of major adverse cardiovascular event in patients with and without MVD. The benefit tended to occur earlier and was larger in patients with MVD. However, the magnitude grew over time in both groups. These data support early initiation of intensive low-density lipoprotein cholesterol lowering both in patients with and without MVD.

Efficacy of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor Treatment for Repeated In-stent Restenosis in a Coronary Artery.

A 57-year-old woman experienced chest pain. A coronary angiogram revealed middle left anterior descending artery stenosis. Despite receiving adequate anti-hyperlipidemia treatment and undergoing percutaneous coronary intervention (PCI), she experienced angina and required PCI six more times for in-stent restenosis. As she had high lipoprotein (a) [LP-(a)] levels at the seventh PCI procedure, proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) was administered, and a reduction in the LP-(a) and low-density lipoprotein cholesterol (LDL-C) values was observed. She experienced no recurrence of angina for five years with PCSK9i treatment. PCSK9i can reduce not only LDL-C but also LP-(a) levels, resulting in cardiac event risk reduction.

Inclisiran, Low-Density Lipoprotein Cholesterol and Lipoprotein (a).

Dyslipidemia treatment is of major importance in reducing the risk of atherosclerotic cardiovascular disease (ASCVD), which is still the most common cause of death worldwide. During the last decade, a novel lipid-lowering drug category has emerged, i.e., proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Apart from the two available anti-PCSK9 monoclonal antibodies (alirocumab and evolocumab), other nucleic acid-based therapies that inhibit or "silence" the expression of PCSK9 are being developed. Among them, inclisiran is the first-in-class small interfering RNA (siRNA) against PCSK9 that has been approved by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of hypercholesterolemia. Importantly, inclisiran therapy may improve low-density lipoprotein cholesterol (LDL-C) target achievement by offering a prolonged and significant LDL-C-lowering effect with the administration of only two doses per year. The present narrative review discusses the ORION/VICTORION clinical trial program that has been designed to investigate the impact of inclisiran on atherogenic lipoproteins and major adverse cardiac events in different patient populations. The results of the completed clinical trials are presented, focusing on the effects of inclisiran on LDL-C and lipoprotein (a) (Lp(a)) levels as well as on other lipid parameters such as apolipoprotein B and non-high-density lipoprotein cholesterol (non-HDL-C). Ongoing clinical trials with inclisiran are also discussed.

Efficacy and tolerability of PCSK9 inhibitors in real-world clinical practice.

Despite widespread use of statins and other lipid-lowering therapies for hypercholesterolaemia, cardiovascular (CV) mortality and morbidity remains high. The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, alirocumab and evolocumab, have been approved for use in patients with familial hypercholesterolaemia and high CV risk in the UK. We reviewed the records of patients at a large health board in Scotland, who were prescribed these agents, to determine their real- world efficacy and tolerability in routine clinical care.

Investigation for statin intolerance reveals possible Charcot-Marie-Tooth disease in a coronary patient: A case report.

Background: Statin regimens are essential for managing lipids and preventing cardiovascular diseases, both in primary and secondary prevention, alongside lifestyle changes. There are, however, some side-effects associated with statin intake, such as an elevation of (CK) and myopathy. Case description: This case describes a coronary patient with high low-density lipoprotein cholesterol (LDL-C) who was undertreated due to elevated creatine kinase (CK) levels and myopathy initially linked to statin use. A proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) replaced statin therapy; however, the existence of persisting/recurrent symptoms or CK elevation posed the need for further investigation. A neurological examination, an electromyography (EMG), and a nerve conduction study (NCV) revealed an underlying sensorimotor polyneuropathy, probably Charcot-Marie-Tooth disease. Conclusions: Persistent muscle symptoms in patients receiving statins should not be always attributed solely to statin intake. Further neurological evaluation could reveal underlying hereditary sensorimotor polyneuropathies. PCSK9i could serve as the therapy of choice in such cases, as additional drug-induced myopathy could pose severe problems for those patients. HIPPOKRATIA 2023, 27 (4):155-157.

Proprotein convertase subtilisin/kexin type 9 inhibitor non responses in an adult with a history of coronary revascularization: A case report.

BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal dominant disorder that is characterized by severely increased low-density lipoprotein (LDL) cholesterol levels. At the same time, elevated LDL levels accelerated the development of coronary heart disease. Several classes of drugs are currently in use to treat FH. Proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) is novel one of these. CASE SUMMARY: This manuscript reports a case of FH that responded modestly after treatment with PCSK9i and statin drugs. Of even more concern is that the patient frequently admitted to the hospital during a 12-year follow-up period. Subsequently, we identified a heterozygous mutation, 1448G>A (W483X) of the LDL receptor (LDLR) in this patient. The serum levels of PCSK9 (proprotein convertase subtilisin/kexin type 9) in the patient was 71.30 ± 26.66 ng/mL, which is close the average level reported in the literature. This LDLR mutation affects LDLR metabolism or structure, which may make it unsuitable for use of PCSK9i. CONCLUSION: Our outcome demonstrates that LDLR-W483X represents a partial loss-of-function LDLR and may contribute to PCSK9i ineffective. In the meanwhile, additional measures are therefore required (particularly with gene sequencing or change the treatment plan) must be initiated as early as possible. Genetic testing for clinically challenging cases who do not respond to PCSK9i therapy is very helpful.

Effects of PCSK9 Inhibitor on Favorable Limb Outcomes in Patients with Chronic Limb-Threatening Ischemia.

AIM: The aim of this study was to examine the effects of evolocumab on favorable limb events in patients with chronic limb-threatening ischemia (CLTI). METHODS: A single-center, prospective observational study was performed on 30 patients with CLTI. The subjects were divided into 2 groups based on evolocumab administration: evolocumab-treated (E) group ( n=14) and evolocumab non-treated (non-E) group (n=16). The primary outcome was 12-month freedom from major amputation. The secondary outcomes were 12-month amputation-free survival (AFS), overall survival (OS), and wound-free limb salvage. The mean follow-up period was 18±11 months. RESULTS: No significant difference was detected between the two groups for the 12-month freedom from major amputation (log-rank p=0.15), while the 12-month AFS rate was significantly higher in the E group than that in the non-E group (log-rank p=0.02). The 12-month OS rate in the E group was shown a tendency for improvement, as compared with that in the non-E group (log-rank p=0.056). Evolocumab administration was not associated with a significant change in freedom from major amputation (HR, 0.23, 95% CI, 0.03-2.07, p=0.19). However, evolocumab administration was related to a tendency for improvement of AFS and OS (HR, 0.13, 95% CI, 0.02-1.06, p=0.056; HR, 0.16, 95% CI, 0.02-1.37, p=0.09, respectively). Moreover, The E group had a higher proportion of wound-free limb salvage at 12 months (92% vs. 42%, p=0.03). CONCLUSION: Evolocumab administration was associated with a better AFS outcome in patients with CLTI. Long-term administration of evolocumab over 12 months contributed to improving proportion of wound-free limb salvage.

Unusual responses to PCSK9 inhibitors in a clinical cohort utilizing a structured follow-up protocol.

OBJECTIVE: To characterize unusual responses to PCSK9 inhibitor (PCSK9i) therapy in a real-world setting, given their extremely low prevalence in clinical trials. METHODS: A retrospective study of patients seen in a structured academic PCSK9i clinic who had LDL-C measurements before and after initiation of PCSK9i (up to 12 months). Unusual response was defined as: (1) no response: no changes in LDL-C level at all time points; (2) delayed response: <30% LDL-C reduction by the third dose, but achieving this threshold at a later time; (3) reduced response: <30% LDL-C reduction at all time points; and (4) lost response: ≥30% LDL-C reduction by the third dose, but displaying <30% reduction at a later time. RESULTS: Of the 411 patients meeting inclusion criteria, 54 were initially classified as unusual responders. After excluding those not adherent to prescribed interventions, 31 patients (7.5%) were classified as true unusual responders. These included: 2 with no response, 12 with delayed response, 3 with reduced response, 6 with delayed or reduced response, 4 with lost response, and 4 with delayed and lost response. Response to PCSK9i therapy at all time points revealed higher on-treatment LDL-C values (94-100 vs. 47-51 â€‹mg/dL, p â€‹< â€‹0.001) and lower degree of percent reduction in LDL-C (23.3-34% vs. 61.1-64.5%, p â€‹< â€‹0.001) in the unusual versus usual responders. Lipoprotein (a) (Lp[a]) values were consistently higher in the unusual responders (81-92.5 vs. 28.5-52 â€‹mg/dL, p â€‹< â€‹0.01). Fold change in post-versus pre-treatment PCSK9 plasma results was similar between the two cohorts (p â€‹> â€‹0.05), suggesting that unusual responses were not due to insufficient plasma PCSK9 blockade. Multiple logistic regression analysis identified clinical FH (OR 2.9, 95% CI 1.27-7.24) and no ezetimibe therapy (OR 0.334, 95% CI 0.150-0.728) as factors related to true unusual response. CONCLUSIONS: Unusual responses to PCSK9i in a clinical cohort are more common than reported in clinical trials. Of the suspected unusual responders, nearly half were the result of adherence issues, and thus careful medication reconciliation should be the first step in diagnosing an unusual response.

Effect of evolocumab therapy on coronary fibrous cap thickness assessed by optical coherence tomography in patients with acute coronary syndrome.

BACKGROUND: The addition of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, evolocumab, to statin therapy produced incremental regression of atherosclerotic plaques and a collaborative prevention of cardiovascular events in patients with coronary artery disease. The effect on fibrous-cup thickness, or extension of the atherosclerotic plaque with PCSK9-inhibitor, for several weeks after onset of acute coronary syndrome (ACS) has never been reported. METHODS: This study aimed to examine the effect of evolocumab on fibrous-cap thickness, as well as the extent of the atherosclerotic plaque, by serial optical coherence tomography (OCT) analysis in patients with ACS. All patients received rosuvastatin 5 mg/day from at least 24 h after onset of ACS. Patients received evolocumab (140 mg every 2 weeks) 1 week after the onset of ACS in the statin plus evolocumab group. Patients took only rosuvastatin in the statin monotherapy group. OCT was performed to assess intermediate, non-culprit lesions just 4 and 12 weeks after emergent percutaneous coronary intervention. RESULTS: OCT analysis revealed that the increase in fibrous-cap thickness and decrease in macrophage grade were greater with a narrower lipid arc and shorter lipid length, which were associated with lower low-density lipoprotein cholesterol (LDL-C) in the statin plus evolocumab group than in the statin alone treatments, even for a short term after ACS onset. CONCLUSIONS: Addition of the PCSK9-inhibitor evolocumab to statin therapy might produce incremental growth in fibrous-cap thickness and regression of the lipid-rich plaque, which were associated with greater reduction of LDL-C even for a short term in the early phase of ACS.

Effect of Preoperative Administration of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor on Carotid Artery Stenting.

BACKGROUND: Perioperative embolic stroke is one of the most serious complications during carotid artery stenting (CAS). Proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) is a low-density lipoprotein-lowering drug that inhibits proprotein convertase subtilisin/kexin type 9, which normally binds to the low-density lipoprotein cholesterol (LDL-C) receptor. Its combination with statin significantly decreases LDL-C levels. PCSK9i is expected to achieve lower LDL-C levels than single use of statin. This study aimed to investigate whether perioperative PCSK9i administration stabilizes carotid artery plaque and reduces perioperative complications of CAS. METHODS: Nine patients with symptomatic stenosis (North American Symptomatic Carotid Endarterectomy Trial [NASCET] 50%) or asymptomatic stenosis (NASCET ≥ 80%) were included. PCSK9i was administered at least twice (once in 2 weeks) in the outpatient clinic before CAS. Perioperative complications; results from blood tests, magnetic resonance imaging (MRI), magnetic resonance angiography, and carotid ultrasonography (US); and modified Rankin scale score at discharge were assessed. RESULTS: High intensity on diffusion-weighted imaging was not observed in 8 patients. Changes in carotid plaque characteristics were found with MRI and/or carotid US in 7 patients. The plaque to muscle ratio decreased in 3 patients. The carotid plaque became hyperechoic in 2 patients, and the fibrous cap was seen more clearly on carotid US. Two patients had findings of stabilized plaque on MRI and carotid US, which indicates that plaque transformation was more stable. CONCLUSIONS: Lowering LDL-C level could reduce ischemic complications, and low LDL-C level affects plaque stability and antithrombus formation. PCSK9i can possibly stabilize carotid plaque and reduce perioperative complications of CAS.

Effects of proprotein convertase subtilisin/kexin type-9 inhibitors on fatty liver.

BACKGROUND: Many studies have investigated the progression of nonalcoholic fatty liver disease (NAFLD) and its predisposing risk factors, but the conclusions from these studies have been conflicting. More challenging is the fact that no effective treatment is currently available for NAFLD. AIM: To determine the effects of proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibitors on fatty infiltration of the liver. METHODS: This retrospective, chart review-based study was conducted on patients, 18-year-old and above, who were currently on PCSK9 inhibitor drug therapy. Patients were excluded from the study according to missing pre- or post-treatment imaging or laboratory values, presence of cirrhosis or rhabdomyolysis, or development of acute liver injury during the PCSK9 inhibitor treatment period; the latter being due to false elevation of liver function markers, alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Radiographic improvement was assessed by a single radiologist, who read both the pre- and post-treatment images to minimize reading bias. Fatty infiltration of the liver was also assessed by changes in ALT and AST, with pre- and post-treatment levels compared by paired t-test (alpha criterion: 0.05). RESULTS: Of the 29 patients included in the study, 8 were male (27.6%) and 21 were female (72.4%). Essential hypertension was present in 25 (86.2%) of the patients, diabetes mellitus in 18 (62.1%) and obesity in 15 (51.7%). In all, patients were on PCSK9 inhibitors for a mean duration of 23.69 ± 11.18 mo until the most recent ALT and AST measures were obtained. Of the 11 patients who received the radiologic diagnosis of hepatic steatosis, 8 (72.73%) achieved complete radiologic resolution upon use of PCSK9 inhibitors (mean duration of 17.6 mo). On average, the ALT level (IU/L) decreased from 21.83 ± 11.89 at pretreatment to 17.69 ± 8.00 at post-treatment (2-tailed P = 0.042) and AST level (IU/L) decreased from 22.48 ± 9.00 pretreatment to 20.59 ± 5.47 post-treatment (2-tailed P = 0.201). CONCLUSION: PCSK9 inhibitors can slow down or even completely resolve NAFLD.