Use Of PCSK9 Inhibitors Research Articles

Residual risk post acute coronary syndroms after 1 year of cardiac rehabilitation. Can we improve it?

Abstract How much do we reduce residual risk with a cardiac rehabilitation program? What is left to do? Which would be the impact of a lower cholesterol threshold for the use of more potent lipid lowering drugs on residual risk? We explored these issues. Methods We retrospectively analyzed clinical and biochemical data from patients after 1 year of cardiac rehabilitation following an acute coronary event. Changes in residual risk of combined myocardial infarction, stroke and cardiovascular death, and its modification with optimization of treatment in patients with suboptimal lipid control, and with the use of PCSK9 inhibitors in those with a LDL-cholesterol over 70 mg/dl, were estimated using the SMART-REACH model calculator. Wilcoson and McNemar tests for paired-samples were used in the statistical análisis. Results 262 consecutive patients were included. Median age was 63.5 years, 80.5% men, 89.3% stented. Baseline use of high intensity statins was 90.8%. After 1 year, the use of Ezetimibe was doubled to 77.1%, empaglifozin to 26%, and PCSK inhibitors were used only in 5%, with a residual use of colchicine. Blood pressure and Cholesterol profile improved after 1 year, with no change in HbA1c. Absolute 10- years and life-long residual risk were reduced 4.8% (95%CI:3.6-5.9) and 6% (95%IC: 4.5-7.5) respectively (both p<0.001). LDL-cholesterol was >55 mg/dl with a suboptimal lipid lowering treatment in 29.8% of patients: an optimization to higher dose of rosuvastatin/atorvastatin plus ezetimibe would decrease absolute 10-years and life-long residual risk in 7.2% (95%CI: 4.9-9.4) and 9.9% (95%CI: 6.4-13.5%) respectively (both p<0.001). LDL-cholesterol remained > 70 mg/dl after higher dose of statin plus ezetimibe in 13.7% of patients: use of PCSK9 inhibitors in this group would reduce absolute 10-year and life-long residual risk in an additional 5.4% (95%CI:2.4-7,6;p=0,018) and 7% (95%CI: 3,8-10,1) compared to maximal dose of statins plus ezetimibe. Conclusions Cardiac rehabilitation programs reduce cardiac risk 1 year after an acute coronary event. Residual risk remain very high, and a significant proportion of patients do not reach recommended targets and optimal lipid lowering treatment. Optimization of lipid lowering drugs, and a lower LDL-cholesterol threshold for the use of PCSK9 inhibitors, would have a significant impact on residual risk.Changes in residual riskPCSK9-inhibitors in LDLchol >70 mg/dl

Correlation of coronary and carotid atheroma volume in patients with severe and familial hypercholesterolemia (VOCCA-3D HF)

Abstract Background Stratifying the risk of CV event of familial hypercholesterolemia (FH) patients is not always simple, as they usually are excluded from CV disease risk estimation scores. It has become increasingly clear over the last several years that the heterogeneity in risk among patients with FH is far greater than previously appreciated. To that end, not all patients with FH will require the use of PCSK9 inhibitors. Aim We described the type of coronary artery disease (CAD) in patients with severe and familial hypercholesterolemia and without known atherosclerotic cardiovascular disease and searched for the best determinants of CAD. We searched for correlation between epicardial adipose tissue and CAD. Methods We evaluated the atherosclerosis burden with a combination of calcium score (CAC), computed tomography angiography, and the quantification of coronary atheroma volume and the analysis of the composition of the plaques, alongside with the use of ultrasonography of supra-aortic trunks with 3D quantification of atheroma volume. We also evaluated epicardial adipose tissue volume with CT. Results We analyzed 89 individuals with LDL-c > 190 mg/dL, with a mean age of 56,7 years. LDL-c burden was high (maximal LDL-c level across life of 2.77 g/L in mean, duration of hypercholesterolemia of 21.5 years in mean). Forty percent of the individuals had a CAC score of zero, and only one patient had non-calcified atheroma despite a CAC score of zero. Among patients with CAD, 50% had a CAC > 100 AU, 9% had a stenosis > 50%. Coronary atheroma volume amounted to a median of 50.9 mm3 in patients with CAD, representing 4% of the analyzed coronary lumen volume, and was mainly made of calcified and non-calcified fibrous plaques. At-risk plaques were not frequent (9% of low-attenuation plaques, 15.2% of positive remodeling and 2% of napkin-ring sign) in patients with CAD. Fifty percent of the individuals had no carotid plaque. Among various clinical and biological risk factors (LDL-year-score, age, blood pressure, smoking, familial history, diabetes), the carotid atheroma volume was the only variable to be independently correlated with both CAC (t=3.1, p=0.006) and coronary atheroma volume (t=4.9, p<0.001). Epicardial adipose tissue was not associated with CAD. Conclusion A significant part of the patients with severe and familial hypercholesterolemia has no CAD, however half of the patients with CAD have an important atherosclerosis burden, which can be well predicted by the carotid atheroma volume. Such a screening could help identify the individuals who would benefit the most from intensive cholesterol-lowering drugs.CAC categoriesType of coronary plaques

12369 Clinical Experience With Inclisiran At An Academic Center

Abstract Disclosure: L. Chavez Marin: None. M. Gonzalez: None. M.F. Linton: None. B.G. Carranza Leon: None. Background: Inclisiran, a small interfering RNA (siRNA) molecule designed to inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9), is the only siRNA approved for management of elevated low-density lipoprotein cholesterol (LDL-C) in both primary (for patients with familial hypercholesterolemia) and secondary prevention of cardiovascular disease. In clinical trials, Inclisiran has been shown to reduce LDL-C by more than 50% in populations at high cardiovascular risk. However, real world data about its tolerability and efficacy is still limited. Methods: We conducted an electronic medical record search to identify subjects who were prescribed Inclisiran at a lipid clinic within Vanderbilt University Medical Center (Nashville, USA). Subjects were included if they received at least one dose of Inclisiran and had pre- and post- LDL-C levels. Subjects taking other LDL-C lowering medications like statins, ezetimibe, bempedoic acid, and PCSK-9 inhibitors were included. Pre- and post- LDL-C averages were calculated and analyzed with 95% confidence intervals. The reasons for medication discontinuation were also examined. Results: Out of 69 subjects identified, only 19 met criteria for inclusion, while 32 never received a dose due to cost burden and insurance denial. The other 18 subjects were not included due to inadequate lab results at the time of data collection. In subjects who received at least one dose of Inclisiran, average pre-LDL-C was 142 mg/dL [CI: 34.7] while post-LDL-C was 77 mg/dL [CI: 24.0], notable for a 46% decrease in LDL-C levels. These subjects were also receiving another lipid lowering agent, like a statin, or had previously used a monoclonal antibody-PCSK-9 inhibitor. Those without prior use of PCSK-9 inhibitors were also analyzed. Average pre-LDL-C was 109.5 mg/dL [CI: 15.8] while post-LDL-C was 39.8 mg/dL [CI: 17.2], which revealed a 64% decrease in LDL-C levels. The main reason for discontinuation of Inclisiran was insurance denial followed by individual preference. Only one subject discontinued Inclisiran due to experiencing a generalized rash. Conclusions: Inclisiran is an effective and overall well-tolerated medication indicated for the management of elevated LDL cholesterol. Our study revealed that for individuals with above goal LDL-C, despite maximum tolerated therapy with a statin, additional LDL-C lowering benefits can be seen with Inclisiran use. However, insurance approval and cost burden seem to be the main barriers for access. Presentation: 6/3/2024

PCSK9 Inhibitors: Is the Time Ripe for the "Fast Track" Use Independently on the LDL-C Baseline Values in Acute Coronary Syndrome?

The low-density lipoprotein cholesterol (LDL-C) lowering decreases the risk to develop major adverse cardiovascular events (MACE) in patients with acute coronary syndrome (ACS). Therefore, the "fast track" use of PCSK9 inhibitors (PCSK9i) has been introduced in ACS patients not achieving LDL-C target (70mg/dl) despite an ongoing lipid lowering therapy with statin at maximum tolerated dosage plus ezetimibe or stain-naïve (LDL-C > 130mg/dl). PCSK9i "fast track" use has shown to achieve the regression of "non-culprit" atherosclerotic plaques leading to a further MACE decrease. Interestingly, it has been also hypothesized a role of PCSK9i beyond the LDL-C lowering in ACS. PCSK9i have been demonstrated to decrease the inflammation of atherosclerotic plaques and myocardium, inhibit platelet aggregation, and improve the cardiomyocyte survival against the reperfusion injury. All these findings may positively impact on the prognosis and suggest the PCSK9i use in the acute phase of ACS independently on the baseline LDL-C values.

Association of PCSK9 inhibitors with mortality: insights from a retrospective cohort analysis.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are effective in reducing cardiovascular events, but their impact on all-cause mortality and medical utilization compared to statins is unclear. This study investigated PCSK9 inhibitor use and its impact on mortality and medical utilization vs. statins, using TriNetX database data with up to 9 years of follow-up. This retrospective cohort study analysed TriNetX data spanning 1 July 2015, to 31 December 2023, including 79194 PCSK9 inhibitor users (alirocumab, evolocumab, inclisiran) and 5437513 statin users with hyperlipidaemia. The primary outcomes were all-cause mortality and medical utilization, including hospital inpatient services, emergency department visits, critical care, and mechanical ventilation. Propensity score matching showed that PCSK9 inhibitor use was associated with a 28.3% lower risk of all-cause mortality [adjusted hazard ratio (aHR) 0.717, 95% confidence interval (CI): 0.673-0.763] and significant reductions in medical utilization (hospital inpatient services usage: aHR 0.692, 95% CI: 0.664-0.721; emergency department services: aHR 0.756, 95% CI: 0.726-0.788; critical care services: aHR 0.619, 95% CI: 0.578-0.664; and mechanical ventilation: aHR 0.537, 95% CI: 0.484-0.596) compared to statins. These findings were consistent across various demographics and clinical subgroups. The sensitivity analyses supported the robustness of the findings. PCSK9 inhibitors significantly reduced all-cause mortality and medical utilization compared to statins, suggesting their important role in dyslipidaemia management, particularly for statin-naïve or intolerant patients. Further research, including randomized controlled trials, is needed to confirm these findings and explore the underlying mechanisms.

Effects of PCSK9 Inhibitors on Early Neurologic Deterioration in Patients with Acute Non-Cardioembolism without Hemorrhagic Transformation After Intravenous Thrombolysis.

END (Early Neurologic Deterioration) significantly elevates the risk of morbidity and mortality. While numerous studies have investigated END following hemorrhagic transformation post-thrombolysis in acute cerebral infarction research on END without hemorrhagic transformations in patients with acute cerebral infarction due to non-cardiogenic embolism remains scarce. This study aimed to elucidate the impact of PCSK9 inhibitors on early neurological deterioration (END) in patients with acute non-cardioembolism cerebral infarction without hemorrhagic transformation post-intravenous thrombolysis. Additionally it aimed to identify risk factors associated with END in patients suffering from this type of stroke. The objective of this study is to investigate the effect of PCSK9 inhibitors on early neurologic deterioration (END) in patients with acute non-cardiogenic cerebral infarction without hemorrhagic transformation after intravenous thrombolysis and identify associated risk factors for END in this patient population. In this retrospective case-control study the data of consecutive patients who underwent intravenous thrombolysis after AIS (acute ischemic stroke) without hemorrhagic transformation during hospitalization at the Stroke Center of The Fifth Affiliated Hospital of Sun Yat-sen University between January 2018 to February 2023 were retrieved and assessed. An increase of >2 in the National Institutes of Health Stroke Scale (NIHSS) within 7 days after admission was defined as END. This study included 250 patients (56 males 22.4%) they were 63.34±12.901 years old. There were 41 patients in the END group and 209 in the non-END group. The usage rate of PCSK9 inhibitors was significantly different between the END group and non-END group (29.268% vs 58.852% P<0.001). The White blood cell count (WBC) and homocysteine levels showed a significant difference between the two groups (all P<0.05). Patients not using PCSK9 inhibitors (OR=0.282 95%CI: 0.127-0.593) and white blood cell count (OR=1.197, 95%CI: 1.085-1.325) were independently associated with END. Receiver-operating characteristic curve analysis suggested that the sensitivity specificity and area under the curve for PCSK9 inhibitors used for END were 88.9%, 80.7% and 0.648 respectively. The use of PCSK9 inhibitors can reduce the incidence of early neurological deterioration in patients with acute non-cardioembolism and non-hemorrhagic transformation after intravenous thrombolysis.

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

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. 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. 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. 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.

Healthcare professionals' perspectives on use of PCSK9 inhibitors in cardiovascular disease: an in-depth qualitative study.

Injectable medicines such as PCSK-9 inhibitors are increasingly used to manage risk factors for cardiovascular events with little information around the perceptions of healthcare professionals (HCPs) on the administrative and clinical practicalities. The aim was to identify the facilitators and barriers on the use of injectable therapies with CV benefits through interviews with HCPs. Qualitative interviews were conducted in the United Kingdom (London and Leeds) and Italy (Rome and Milan) in 2021. Coding was undertaken using NVivo and thematic analysis performed. A total of 38 HCPs were interviewed, 19 in each country composing of physicians (n = 18), pharmacists (n = 10), nurses (n = 9) and pharmacy technician (n = 1). Four themes emerged: (i) Clinicians' previous experiences with injectable therapies (ii) Challenges with patients' behaviours and beliefs (iii) Clinicians' knowledge of injectable therapies and therapeutic inertia and (iv) Organisational and governance issues. The behaviour and beliefs from healthcare professionals focused on facilitating behaviour change as well as the poor interdisciplinary working and collaboration. Therapeutic inertia was raised where physicians either lacked awareness of injectable therapies or were unwilling to prescribe them. The importance of facilitating patient education on injection techniques was highlighted while organisational and governance issues identified the lack of guidance to inform practice. Clear pathways are required to identify those who were eligible for injectable therapies as well as on how injectables should be prescribed. If medicine optimisation is to be achieved, there needs to be structured processes in place to identify eligible patients and the development of educational material.

Drug Target Mendelian Randomization Study of PCSK9 and HMG-CoA Reductase Inhibition and Atrial Fibrillation

Introduction: Atrial fibrillation (AF) is a prevalent cardiac arrhythmia with significant clinical implications. The potential influence of lipid-lowering therapies, specifically PCSK9 inhibitors (PCSK9i) and HMG-CoA reductase inhibitors (statins), on AF risk remains a topic of interest. This mendelian randomization (MR) study aimed to elucidate the causal relationship between genetically predicted inhibition of PCSK9 and HMG-CoA reductase and the risk of AF. Methods: Utilizing publicly available, summary-level genome-wide association study data, we employed single-nucleotide polymorphisms associated with lower LDL-C levels as instruments for gene-simulated inhibition of PCSK9 and HMG-CoA reductase. Multiple MR techniques were applied to estimate the causal effects, and sensitivity analyses were conducted to validate the results. Results: Genetically predicted inhibition of PCSK9 demonstrated a reduced risk of AF, with an odds ratio (OR) of 0.92 (95% CI: 0.85–0.99, p = 0.01) using the inverse variance-weighted (IVW) method. In contrast, the inhibition of HMG-CoA reductase did not exhibit a statistically significant association with AF risk (IVW: OR = 1.11, 95% CI: 1.00–1.22, p = 0.05). Conclusion: Our MR study suggests that genetically predicted inhibition of PCSK9, but not HMG-CoA reductase, is associated with a lower risk of AF. These findings provide evidence for a causal protective effect of PCSK9i on AF and support the use of PCSK9i for AF prevention in patients with dyslipidemia. Further studies are needed to elucidate the mechanisms underlying the differential effects of PCSK9i and statins on AF and to confirm the clinical implications of our findings.

Genetically proxied low-density lipoprotein cholesterol lowering via PCSK9-inhibitor drug targets and risk of congenital malformations.

Current guidelines advise against the use of lipid-lowering drugs during pregnancy. This is based only on previous observational evidence demonstrating an association between statin use and congenital malformations, which is increasingly controversial. In the absence of clinical trial data, we aimed to use drug-target Mendelian randomization to model the potential impact of fetal LDL-lowering, overall and through PCSK9 drug targets, on congenital malformations. Instrumental variants influencing LDL levels overall and through PCSK9-inhibitor drug targets were extracted from genome-wide association study (GWAS) summary data for LDL on 1 320 016 individuals. Instrumental variants influencing circulating PCSK9 levels (pQTLs) and liver PCSK9 gene expression levels (eQTLs) were extracted, respectively, from a GWAS on 10 186 individuals and from the genotype-tissue expression project. Gene-outcome association data was extracted from the 7th release of GWAS summary data on the FinnGen cohort (n = 342 499) for eight categories of congenital malformations affecting multiple systems. Genetically proxied LDL-lowering through PCSK9 was associated with higher odds of malformations affecting multiple systems [OR 2.70, 95% confidence interval (CI) 1.30-5.63, P = 0.018], the skin (OR 2.23, 95% CI 1.33-3.75, P = 0.007), and the vertebral, anorectal, cardiovascular, tracheo-esophageal, renal, and limb association (VACTERL) (OR 1.51, 95% CI 1.16-1.96, P = 0.007). An association was also found with obstructive defects of the renal pelvis and ureter, but this association was suggestive of horizontal pleiotropy. Lower PCSK9 pQTLs were associated with the same congenital malformations. These data provide genetic evidence supporting current manufacturer advice to avoid the use of PCSK9 inhibitors during pregnancy.

The impact of early in-hospital use of PCSK9 inhibitors on cardiovascular outcomes in acute coronary syndrome patients: A systematic review and meta-analysis

ObjectiveTo explore the safety and assess the cardiovascular impact of early in-hospital administration of PCSK9 inhibitors in patients with acute coronary syndrome (ACS). MethodsA systematic search of PubMed, Web of Science, and Embase databases was conducted for studies involving the use of PCSK9 inhibitors in ACS patients from inception to October 2023. Two independent researchers screened the literature, extracted data, and assessed the risk of bias in the included studies. Meta-analysis was performed using STATA 16.0 software. ResultsNine studies, encompassing a total of 2896 ACS patients, were included in the analysis. When compared to statin monotherapy, early administration of PCSK9 inhibitors during hospitalization for ACS proved effective in reducing the incidence of major adverse cardiovascular events (MACEs). This encompassed a decrease in coronary revascularization [Relative Risk (RR) = 0.78, 95% CI (0.62, 0.98), P < 0.05], recurrent ACS [RR = 0.62, 95% CI (0.42, 0.94), P < 0.05], readmissions due to unstable angina [RR = 0.71, 95% CI (0.59, 0.85), P < 0.01], and strokes [RR = 0.31, 95% CI (0.09, 1.04), P = 0.058]. There was no significant difference in the incidence of death between the two groups.The use of PCSK9 inhibitors notably hastened the reduction of LDL-C, TG, and Non HDL-C levels in the short term. Additionally, it increased HDL-C levels and the number of individuals meeting LDL-C compliance criteria. Importantly, the risk of adverse drug events, such as ALT increase >3xULN, allergies, and musculoskeletal pain, did not significantly elevate with PCSK9 inhibitor use. ConclusionThe early administration of PCSK9 inhibitors has been found to safely and effectively lower diverse lipid levels in patients with ACS. This reduction is associated with a noteworthy decrease in MACEs, encompassing revascularization, recurrent ACS, and hospital readmissions.

Association between PCSK9 inhibitors and acute kidney injury: a pharmacovigilance study.

PCSK9 inhibitors are a novel class of lipid-lowering medications, and numerous clinical studies have confirmed their significant role in improving the progression of chronic kidney disease. However, recent case reports have indicated new evidence regarding their association with acute kidney injury (AKI), with some patients experiencing acute tubular injury after PCSK9 inhibitors use. To clarify the relationship between PCSK9 inhibitors and AKI, we conducted a pharmacovigilance study. Using the Food and Drug Administration Adverse Event Reporting System (FAERS) database from the third quarter of 2015 to the fourth quarter of 2022, a disproportionality analysis was employed to identify adverse events suggestive of AKI after PCSK9 inhibitors use. The drugs of interest included evolocumab and alirocumab. A total of 144,341 adverse event reports related to PCSK9 inhibitors were analyzed, among which 444 cases were suspected of AKI for evolocumab, and 172 cases for alirocumab. Evolocumab had a greater impact on AKI in males (ROR 1.4, 95% CI 1.54-1.69). The ROR and 95% CI for evolocumab and Alirocumab were 0.13 (0.12-0.14) and 0.26 (0.23-0.30) respectively. Further analysis of AKI associated with the concomitant use of PCSK9 inhibitors with cephalosporins, furosemide, torsemide, pantoprazole, omeprazole, and esomeprazole revealed ROR and 95% CI of 0.38 (0.23-0.62), 0.38 (0.31-0.48), 0.18 (0.08-0.38), 0.23 (0.17-0.29), 0.20 (0.16-0.26), and 0.14 (0.10-0.20) respectively. Through the FAERS database, we analyzed the clinical characteristics of AKI associated with PCSK9 inhibitors, exploring its risks. Our findings suggest that PCSK9 inhibitors might have a potential protective effect against AKI and exhibit similar effects when co-administered with other nephrotoxic drugs.

Optimizing PCSK9 Inhibitor Integration for Cardiovascular Disease Management in Pakistan.

Cardiovascular illnesses (CVDs), particularly Coronary Artery Disease (CAD) and Ischemic Heart Disease (IHD), are major global health burdens, with a growing incidence in Pakistan. The development of PCSK9 inhibitors offers encouraging advantages in lowering LDL cholesterol and lowering cardiovascular risk, even though conservative treatments are still essential. However, access to them is severely hampered by their high cost, especially in environments with little resources. The financial limitations and scarcity of healthcare resources while examining the difficulties in obtaining PCSK9 inhibitors in Pakistan is essential. In order to develop solutions for affordability and fair access, it emphasizes the urgent need for multi-stakeholder collaboration, including governmental action, healthcare sector involvement, and pharmaceutical company engagement. It also emphasizes the need for data-specific research and the use of PCSK9 inhibitors in conventional treatment protocols.

The potential future role of extensive lipid lowering in ACS patients with the use of PCSK9 inhibitors: early bird catches the worm.

The potential future role of extensive lipid lowering in ACS patients with the use of PCSK9 inhibitors: early bird catches the worm.

Evaluating risk-based allocation strategies for PCSK9 inhibitors: results from a simulation study in a contemporary ASCVD cohort

Abstract Background/Aim Targeting PCSK9 inhibitors (PCSK9i) to patients with high LDL-cholesterol (LDL-C) as well as a high cardiovascular event rate yields the highest therapeutic effect and is thus reasonable from a health economic perspective. The current European dyslipidaemia guideline determines PCSK9i eligibility solely by LDL-C, whereas guidelines from the US/the UK additionally use a set of clinical risk factors. Such selection criteria require evaluation. Methods We determined the cardiovascular event rate and calculated the cost/preventable cardiovascular event for PCSK9i initiation in the target populations according to three scenarios: (i) European Society of Cardiology (ESC) 2019 dyslipidaemia guideline (PCSK9i recommended for all patients with residual LDL-C &amp;gt;55 mg/dl), (ii) American Heart Association/American College of Cardiology (AHA/ACC) 2018 cholesterol guideline (use of PCSK9i restricted to patients with residual LDL-C &amp;gt;70 mg/dl and clinical risk factors) and (iii) UK National Institute for Health and Care (NICE) recommendation (use of PCSK9i restricted to patients with residual LDL-C &amp;gt;155 mg/dl or &amp;gt;135 mg/dl with clinical risk factors). A Monte Carlo simulation taking into account statin intolerance was used to simulate uptitration of lipid lowering medications according to the different scenarios. Analyses were based on patients with atherosclerotic cardiovascular disease (ASCVD) from a contemporary all-comers cohort recruited at a large tertiary care center in Germany. Major adverse cardiovascular events (MACE, defined as the composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) were recorded over a median follow-up of 4.2 years. Results We included 1922 patients with ASCVD (mean age 69.3 years, median baseline LDL-C 86.0 mg/dl, 75.0% male). Eligibility for PCSK9i was simulated to be 39.6% (ESC 2019), 6.2% (AHA/ACC 2018) and 1.4% (NICE). The 3 year cardiovascular event rates in the corresponding PCSK9i target populations were 11.4%, 13.8% and 13.8% respectively. Event rate differences were driven by a higher rate of non-fatal myocardial infarction in the risk-based target populations (5.2%, 8.2%, 7.2%). Annual cost/preventable event differed by up to a factor 3 (689,000 €, 515,000 € and 215,000 €), driven mainly by pre-PCSK9i LDL-C levels in the different target populations (68.8 mg/dl, 76.0 mg/dl and 182.7 mg/dl). (Table 1) Conclusion The AHA/ACC and NICE guidelines, based on both residual LDL-C and clinical risk factors, reduced the eligibility for PCSK9i as well as the cost/preventable cardiovascular event compared to the ESC guideline. However, the clinical criteria used for risk classification yielded limited discrimination for the identification of subpopulations at highest cardiovascular risk. Development of accurate risk prediction tools and their integration into risk-based allocation strategies, both requisites for a cost-effective use of PCSK9i, remain a challenge.Table 1

Abstract 14234: Fast Track Use of PCSK9i in Acute Coronary Syndromes in Real World Practice. Insights From the AT-TARGET-IT Registry

Introduction: In patients with recent acute coronary syndrome (ACS), PCSK9 inhibitors (PCSK9i), alirocumab and evolocumab, intensively decrease LDL-C and determine reduction of ischemic events. Yet, scant data are available on the initiation of PCSK9i in ACS patients in real-world setting. Aim: AT-TARGET-IT is an Italian multicenter prospective phase 4 registry involving 23 centers, designed to assess efficacy, safety and adherence of PCSK9i, as well as clinician’s behavior on lipid lowering therapies (LLT) in patients at very high CV risk. Aim of the current analysis is to report efficacy and safety in patients suffering ACS who received early prescription of PCSK9i during hospital stay, according to national reimbursement rules. Methods: From March 2020 through May 2023, we enrolled patients receiving PCSK9i as part of their optimal medical therapy. Clinical, laboratory and demographic characteristics and concomitant therapies were recorded at the time of first prescription and in subsequent follow-up. Results: We report 405 patients (22% female, age 61 years, 60% chronic coronary syndromes). Median LDL-C was 142 mg/dL at hospital admission, reached 45 mg/dL at first control (time 37 days, 67% reduction, 97 mg/dl absolute reduction) and remained unchanged at latest lipid control (time 11 months, 66% reduction, 94 mg/dl absolute reduction). Of 405 patients enrolled, 252 patients (62%) were receiving LLT at time of hospital admission, of them 91 (36%) were on ezetimibe, 48 (19%) on statin and 113 (45%) were on a statin and ezetimibe combination. LDL-C target according to the ESC guidelines was reached in 272 patients (67%), with differences based on LLT (Figure 1-A). Also LDL-C percentage reduction was influenced by background LLT (Figure 1-B). No serious adverse reactions were reported. Conclusions: Early PCSK9i administration effectively reduces LDL-C in ACS patients in the real-world setting. However, concomitant LLT is needed to optimize early LDL.values.

Abstract 17162: High Lp(a) is Associated With Activation of the Arachidonic Acid Pathway

Introduction: High lipoprotein(a) [Lp(a)] is associated with increased platelet aggregation, inflammation and cardiovascular events. Eicosanoids such as eicosapentaenoic acid (EPA) and arachidonic acid (AA) have anti- and pro-inflammatory effects, respectively. In this cross-sectional study, we explored the associations between eicosanoids, Lp(a), and oxidized phospholipids on apolipoprotein B (oxPL:apoB). Hypothesis: Increased platelet aggregation and inflammation associated with high Lp(a) levels may be due to relative EPA and AA levels. Methods: Consecutive outpatients with known Lp(a) levels seen in an outpatient cardiology practice between April 2021 to April 2023 underwent repeat testing for Lp(a) and measurement of OxPL:apoB, EPA and AA levels. OxPL:apoB was measured using chemiluminescent immunoassay. Fatty acid measurements were done via column chromatography/mass spectrometry. Lp(a), OxPL-apoB, EPA, and AA were log e -transformed to satisfy the assumption of normality. Results: We enrolled 238 patients with a mean age of 56.5 ± 13.5 years (46% being female, 69% white, 10% black, 14% Asian). Statin therapy was used in 66%, and mean LDL-C was 87.3 ± 47.5 mg/dL. Median (IQR) Lp(a), OxPL:apoB, AA, and AA:EPA ratio was 167.7 (57.3-233.5) nmol/L, 2.3 (1.2-3.9) nmol/L, 287.3 (234.8-350.2) ug/mL, and 10.3 (6.1-14.9), respectively. Lp(a) correlated with OxPL:apoB (r=0.48, p&lt;0.0001). In multivariate analysis adjusting for age, race, sex, hypertension, LDL-C, statin use and PCSK9 inhibitor use, log-Lp(a) was associated with AA (p=0.002) and log-AA:EPA (p=0.02), but not associated with log-EPA (p=0.19). LogOxPL:apoB was associated with log AA (p=0.03). Conclusion: Higher Lp(a) levels are associated with elevated AA levels, suggesting a pathway by which Lp(a) may contribute to increased platelet aggregation and inflammation in patients with high Lp(a).

FRI086 Statin Use After Lobar Intracerebral Hemorrhage- Is It Safe?

Abstract Disclosure: D. Vedamurthy: None. M. Ambrosino: None. K. Suri: None. D. Soffer: None. D. Jacoby: None. Background: Observational studies and randomized clinical trials have yielded conflicting data on the role of statins in causing intracerebral hemorrhage. It is unclear whether it is safe to continue statins in patients who have atherosclerotic cardiovascular disease (ASCVD) when they sustain an intracerebral hemorrhage (ICH). It is also not clear whether this risk of ICH (if present) relates to statin use or “too low” levels of LDL-C. Case: 75-year-old female with history of hypertension, hyperlipidemia, and a coronary artery calcium score of 450, presented to the hospital with severe headache and was diagnosed to acute right ICH. She did not smoke, use street drugs or drink excess alcohol. She did not have a family history of premature ASCVD. Her other medication included amlodipine, rosuvastatin and aspirin. Her lipid panel at hospitalization was TC 130 mg/dl, HDL 38 mg/dl, TG 137 mg/dl and LDL-C 70 mg/dl. Imaging studies were negative for cortical venous thrombosis, reversible cerebrovascular constriction, vasculitis, aneurysm, or AV fistula as etiologies. TEE was negative for cardioembolic source. Her hypertension medications were optimized, and she was discharged without any statin therapy. She fortunately recovered with mild deficits. She enrolled in an open-label randomized study- SATURN- which aims to assess safety of statin use in recurrent ICH. Her lipid panel while off statins showed a TC 274 mg/dl, TG 159 mg/dl, markedly elevated LDL-C of 197 mg/dl, and HDL-C 47 mg/dl. She presents to the lipid clinic for risk reduction. Early studies suggested increased ICH related to very low LDL-C levels, especially in the East Asian population. Concerns about statin use and ICH sparked after post-hoc analyses of SPARCL. Data from mendelian randomization studies and meta-analysis have failed to show convincing associations between statin use and ICH. Certain genetic variants, especially related to Apo E, have been shown to enhance this risk for ICH. There is a diversity in management of patients who have sustained an ICH (especially the lobar type as opposed to deep). An open label randomized trial (SATURN) is currently recruiting patients to answer this unresolved question. The dilemma is compounded in patients who have comorbid ASCVD. There are signals that PCSK9 inhibitors may be safer in terms of less propensity to cause intracerebral hemorrhage, but more data is needed. Moreover, the very low LDL-C levels achieved with use of PCSK-9 inhibitors may be concerning. Conclusion: There are no clear major society guidelines to advice clinicians on the best way to manage patients who have sustained a lobar intracerebral hemorrhage and have a compelling reason to be on statins for lipid lowering therapy to treat ASCVD. There are no clear guidelines on how low is “too low” as far as LDL-C targets are concerned. We present this case study as a call for more robust and expedient research in this field. Presentation: Friday, June 16, 2023

Feasibility and efficacy of PCSK9 inhibitors in cases of statin therapy limitation or intolerance

Cardiovascular diseases are a common cause of death throughout the world, and in Russia this figure reaches high values as well. The main cause of cardiovascular pathologies is atherosclerosis, which develops against the background of lipid metabolism disorders, in particular, the accumulation of low-density lipoprotein cholesterol. Statins are the main drug in the complex therapy of dyslipidemia, however, their limited use in patients with diagnosed diabetes mellitus and statin intolerance reduces the possibilities and effectiveness of adequate long-term therapy for hyperlipidemia. PCSK9 inhibitors are promising drugs in terms of efficacy, nevertheless, the question of the possibility of using these drugs in patient groups with statin limitations arises. The purpose of the review. This article provides information on the use of PCSK9 inhibitors in the largest populations with limitations to statin therapy (patients with diabetes mellitus and patients with statin intolerance). We identified potentially relevant studies by searching the electronic databases MEDLINE, SCOPUS, PubMed, Google Scholar, and the Cochrane Database of Systematic Reviews over the last 5 years up to March 2023 using the terms: dyslipidemia, hyperlipidemia, atherosclerosis, PCSK9 inhibitor, statins, low-density lipoproteins, cholesterol, efficacy, safety, therapy. Further, according to the inclusion and exclusion criteria, as well as independent selection, all authors of this article selected the sources that met the criteria and compiled this review. Results. PCSK9 inhibitors are generally a safe, well tolerated, and effective therapeutic strategy with an established role in the therapeutic treatment of hyperlipidemias. Theoretically, PCSK9 inhibitors can be used as an alternative to statin therapy for groups of patients with statin intolerance and those with diagnosed diabetes mellitus, as well as in risk groups. As the experience with using PCSK9 inhibitors in the Russian Federation is growing rapidly, future trials are expected to shed light on their long-term safety and tolerability. On the other hand, other potential therapeutic strategies targeting PCSK9 are being developed, including inclisiran, already registered in the Russian Federation, which is also promising in the treatment of lipid metabolism disorders.

Differences in treatment strategies for LDL-cholesterol reduction in a university lipid clinic vs. standard care apart from the use of PCSK9 inhibitors

Lipid-lowering therapy (LLT) in patients with cardiovascular disease (CVD) is insufficient despite clear guideline recommendations. Lipid clinics have specialized in patients with dyslipidemia, but the magnitude and reduction of low-density lipoprotein cholesterol (LDL-C) in lipid clinics has not yet been studied in depth. To assess LDL-C reduction in very high-risk CVD patients achieved in a lipid clinic through different forms of LLT in comparison to standard care without the initiation of PSCK9 inhibitors. Data from 96 lipid clinic patients were analyzed retrospectively and compared to 84 standard care patients. Very high-risk patients were defined according to the European Society of Cardiology (ESC). Different combinations of LLT focusing on statins and ezetimibe were investigated. Achievement of LDL-C treatment goals according to ESC guidelines as well as LDL-C reduction were assessed. Baseline and follow-up data of 180 very high-risk CVD patients (mean age 67.7 (±9.8) y; 60.6% male) were used. Achievement of the LDL-C goal in lipid clinic patients increased significantly from 14.6% at baseline to 41.7% at the latest visit (p<0.001) while standard care patients improved from 21.4% to 33.3% (p=0.08). The largest relative LDL-C reduction via an adjustment in LLT was achieved by initiation of high-intensity statins (50.8 ± 4.9%, n=5, p < 0.05). Treatment in a lipid clinic leads to a superior LDL-C goal achievement in very high-risk CVD patients as compared to standard care with the highest reduction under LLT with high-intensity statins and ezetimibe. Referral algorithms have to be established for high-risk patients.