Stable Atherosclerotic Disease Research Articles

Effects of rivaroxaban on vascular endothelial function and circulating endothelial progenitor cells: a randomized controlled trial

Abstract Background Combination of low dose rivaroxaban with aspirin was shown to reduce major adverse cardiovascular events when compared to aspirin monotherapy in COMPASS trial. The beneficial effect of rivaroxaban beyond factor Xa inhibition remains unknown. Purpose This randomized controlled trial explored the effects of rivaroxaban on vascular endothelial function and circulating endothelial progenitor cells in patients with stable atherosclerotic disease. Methods An investigator-initiated, investigator-blinded, single-center randomized clinical trial was conducted from May 2021 to August 2023. 142 patients were randomized in 1:1 ratio to receive rivaroxaban 2.5mg twice daily plus aspirin 100mg once daily (Treatment Group) or aspirin 100mg once daily (Control Group) and had follow-up for 3 months. The primary outcome was change of flow mediated dilation (FMD) from baseline to 3-month follow-up. Key secondary outcomes included change of circulating endothelial progenitor cells (CD45+/34+/133+, CD45+/34+/KDR+), platelet activation marker (CD41+/62p+), inflammatory marker (CD14+/11b+) and thrombo-inflammatory maker (CD14+/42b+) measured by flow cytometry, as well as platelet function (aspirin reaction unit, ARU) measured by blood biochemistry. Intention-to-treat analysis was performed with analysis of covariance (ANCOVA) and P < 0.05 was considered statistically significant. Results Overall, 142 patients were enrolled in the study. One patient was excluded from analysis due to protocol deviation. Among the remaining 141 patients (78.8% male and mean age 69±9 years), there were 71 in Treatment Group and 70 in Control Group. The recruited patients had a high prevalence of cardiovascular comorbidities including 76.6% with hypertension, 50.4% with hyperlipidemia, 45.4% with diabetes, and 92.2% with percutaneous coronary intervention. At 3 months, Treatment Group had greater FMD improvements (+2.18±5.66% vs +1.57±5.07%, P=0.03), and more reduction in platelet activation marker (-0.33±13.55% vs +5.78±21.60%, P=0.01). There was no significant change in circulating endothelial progenitor cells, inflammatory marker, thrombo-inflammatory maker, and platelet function. Minor bleeding occurred in 2 patients (2.82%) in Treatment Group and none in Control Group (P>0.05). Conclusion In patients with stable atherosclerotic disease, addition of rivaroxaban to aspirin was well tolerated, and it improved vascular endothelial function and reduced platelet activation.

Clinical Performance and Persistence on Dual Pathway Inhibition with Rivaroxaban and Aspirin in Real-World Setting.

The dual pathway inhibition (DPI) with low-dose rivaroxaban and aspirin in patients with stable atherosclerotic vascular disease reduces the occurrence of cardiovascular events, with no significant increase of intracranial or other critical organ bleedings. Our observational study aimed to describe the clinical performance, adherence, and persistence of DPI therapy among a real-world setting of patients with an established diagnosis of coronary artery (CAD) and/or peripheral artery disease (PAD). We prospectively included all consecutive patients with an established diagnosis of CAD and/or PAD treated with aspirin (ASA) 100 mg once daily and rivaroxaban 2.5 mg twice daily. Clinical evaluation was performed at baseline, before starting treatment, at 1 month, and every 6 months after the study drug administration. A total of 202 consecutive patients (mean age 66 ± 10 years; male 80%) eligible to DPI therapy were included. During a mean follow-up of 664 ± 177 days, the incidence rate of major bleedings and of major adverse cardiovascular events was 0.8 and 1.1 per 100 patients/year, respectively. The adherence to pharmacological treatment was 99%. Additionally, 13.4% of patients suspended the DPI therapy during the follow-up. Minor bleedings resulted the most common cause of both temporary and permanent DPI therapy discontinuation. This observational study supports the safety of DPI with low-dose rivaroxaban and aspirin among patients with CAD and PAD in a real-world setting, showing high persistence and maximum adherence to medical treatment.

Efficacy and safety of drugs in residual cardiovascular risk: A systematic review of the literature

BackgroundThe objective of this research is to evaluate the efficacy and safety of drugs in the residual risk in any of its three components: lipid, inflammatory and thrombotic risk. MethodsA systematic review was conducted of randomized clinical trials that included as a primary outcome, at least one of the conditions related to atherosclerotic cardiovascular disease. The databases used were PUBMED/MEDLINE, Scopus and ClinicalTrials.gov. The risk of bias of the studies was assessed using the Risk of Bias 2 tool. Resultsand discussion: 18 studies were included in the analysis. Half of the studies had low risk of bias or some concerns. Several drugs were effective in reducing the primary outcome: ethyl eicosapentaenoeic acid (17.2 % E-EPA versus 22 % placebo HR: 0.75; 95 % CI 0.68–0.83; p < 0.001), colchicine in stable coronary artery disease (6.8 % vs placebo 9.6 %, HR 0.59, 95 % CI 0.57–0.83; p < 0.001), Canakinumab (150 mg vs placebo ARR 15 %, HR 0.85, 95 % CI 0.74–0.98; p = 0.021) and Rivaroxaban with Aspirin in stable atherosclerotic disease (4.1 % versus aspirin 5.4 %, HR 0.76, 95 % CI 0.66–0.86, P < 0.001). Serious adverse events did not differ between study groups, except for a higher rate of bleeding with the use of combination antithrombotic therapy. ConclusionThe residual risk can be reduced through the use of different drugs that act by modifying atherogenic lipid levels, modulating inflammatory pathways and the risk of thrombosis, with an acceptable safety profile in most studies.

Lipoprotein(a) and the risk of major adverse limb events in patients with stable atherosclerotic vascular disease

Abstract Background/Introduction Patients with atherosclerotic vascular disease are at heightened risk of ischemic events, including adverse limb events. The pathobiology of adverse limb events ranges from events that are predominantly thrombotic such as acute limb ischemia (ALI) to those that are due primarily to progressive atherosclerosis such as worsening functional imitation requiring elective peripheral revascularization and development of critical limb ischemia (CLI). Evolving data suggest that lipoprotein(a) [Lp(a)] may be associated with the risk of adverse limb events; however, which type of events are related to Lp(a) has not been well described. Purpose To evaluate the association between Lp(a) and specific limb outcomes in patients with stable atherosclerotic vascular disease. Methods Data from two randomized clinical trials including patients with stable atherosclerotic vascular disease were combined: TRA2P-TIMI 50 and FOURIER. We measured Lp(a) in baseline samples in the TIMI Clinical Trials Laboratory. Major adverse cardiovascular events (CV death, myocardial infarction (MI), or stroke) were the primary or key secondary outcomes of the trials. Peripheral revascularization procedures occurring during follow up were investigator reported. Adverse limb events, including CLI and ALI, were categorized through the review of safety data by two blinded vascular specialists. MALE was defined as the composite of peripheral revascularization, CLI, or ALI. The association of Lp(a) as a continuous variable and MALE was assessed and adjusted for randomized therapy in each trial, age, sex, race, region, prior MI, prior stroke, peripheral artery disease, hypertension, diabetes mellitus, smoking status, and statin use. Results A total of 28,892 patients were included in the combined analysis population. The median Lp(a) was 36 nmol/L (IQR 12 – 159). A total of 1336 MALE events occurred during follow-up, including 1307 peripheral revascularizations (1237 elective, 173 urgent), 259 CLI events, and 148 ALI events. Lp(a) was associated with an increased risk of MALE (Adj HR 1.07 per SD, 95% CI 1.02 – 1.13, p=0.007, Figure Panel A) with the risk of a similar magnitude for that of MACE (Adj HR 1.05 per SD, 95% CI 1.01 – 1.10, p=0.020). The association of Lp(a) and MALE was driven by peripheral revascularizations including elective revascularization (Adj. HR 1.07, 95% CI 1.02 – 1.13, p=0.010) with a consistent trend for CLI; however, a relationship with ALI was unclear (Figure Panel B). Conclusion In patients with stable atherosclerotic vascular disease, Lp(a) is associated with MALE with the relationship driven by peripheral revascularization and a consistent trend for CLI. Any relationship with ALI, a primarily thrombotic event, is less clear. Overall, these data support the relationship of Lp(a) and progression of lower extremity atherosclerosis.Figure Panel AFigure Panel B

Early initiation of PCSK9 inhibitor therapy versus placebo in patients with acute coronary syndrome: a systematic review and meta-analysis

Abstract Background In patients with stable atherosclerotic cardiovascular disease (ASCVD) and prior atherosclerotic events, PCSK9 inhibitors (PCSK9i) have shown a 50-60% reduction in LDL-C from baseline, on a background of high-intensity or maximally tolerated statin therapy, leading to a 15% relative reduction in the incidence of major adverse cardiovascular events. However, less is known about the impact of PCSK9i initiation acutely in the setting of an acute coronary syndrome (ACS). Purpose To assess the efficacy of early initiation of PCSK9i therapy in lipid parameters among patients presenting with ACS. Methods We performed a systematic review and meta-analysis comparing PCSK9i with placebo in the setting of ACS, added to guideline directed high-intensity or maximally tolerated statin therapy. Inclusion was restricted to randomized controlled trials (RCTs) with initiation of PCSK9i or placebo within 1 week of presentation or percutaneous coronary intervention for ACS. PubMed, EMBASE, and Cochrane Central were searched. The systematic review and meta-analysis followed Cochrane and PRISMA recommendations. Results Six RCTs with a total of 996 patients were included, of whom 503 (50.5%) received PCSK9i. Mean follow-up ranged from 4 to 52 weeks. Mean time from presentation to administration of first dose ranged from 3.6 hours to 6.5 days. LDL-C levels were significantly lower at follow-up in the PCSK9i group (mean difference [MD] -44 mg/dL; 95% CI -54.3 to -33.8 mg/dL; p&amp;lt;0.001; Figure 1A). Lp(a) was also significantly decreased with PCSK9i therapy (MD -24.0 nmol/L; 95% CI -43.0 to -4.9 nmol/L; p=0.01; Figure 1B). Similarly, total cholesterol (MD -49.2 mg/dL; 95% CI -59 to -39.3 mg/dL; p&amp;lt;0.001) and triglycerides (MD -19 mg/dL; 95% CI -29.9 to -8.2 mg/dL; p&amp;lt;0.001) were significantly reduced with PCSK9i therapy, respectively. HDL-C was marginally increased in this same group (MD 2.5 mg/dL; 95% CI 0.9 to 4.2 mg/dL; p=0.003). Conclusions In patients with ACS, early initiation of PCSK9i, in addition to statin therapy, leads to a significant reduction in LDL-C and Lp(a) as compared with placebo. Whether the differences in these lipoproteins translate into a reduction in clinical endpoints is yet to be determined.

Early Initiation of PCSK9 Inhibitor Therapy Versus Placebo in Patients With Acute Coronary Syndrome: A Systematic Review and Meta-Analysis

In patients with stable atherosclerotic cardiovascular disease, proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9is) have shown a 50% to 60% reduction in low-density lipoprotein cholesterol (LDL-C) from baseline when added to high-intensity statin therapy. However, less is known about the impact of PCSK9is in the setting of an acute coronary syndrome (ACS). Therefore, we performed a systematic review and meta-analysis comparing PCSK9is with placebo in the setting of ACS added to guideline-directed high-intensity or maximally tolerated statin therapy. We included randomized controlled trials with initiation of a PCSK9i or placebo within 1week of presentation or percutaneous coronary intervention for ACS. PubMed, EMBASE, and Cochrane Central were searched. This study followed the Cochrane and Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) recommendations. A total of 6 randomized controlled trials were included, with a total of 996 patients, of whom 503 (50.5%) received PCSK9is. The mean follow-up ranged from 4 to 52weeks. The LDL-C (mean difference [MD] -44.0mg/100ml, CI -54.3 to -33.8, p <0.001) and lipoprotein (a) levels (MD -24.0nmol/L, confidence interval [CI] -43.0 to -4.9, p = 0.01) were significantly lower at follow-up with PCSK9is. Similarly, the total cholesterol (MD -49.2mg/100ml, CI -59.0 to -39.3), triglycerides (MD -19.0mg/100ml, CI -29.9 to -8.2), and apolipoprotein B (MD -33.3mg/100ml, CI -44.4 to -22.1) were significantly reduced with PCSK9is. In conclusion, in patients with ACS, early initiation of PCSK9i added to statin significantly reduces LDL-C and lipoprotein (a) levels compared with placebo. Whether the differences in these atherogenic lipoproteins translate into a reduction in clinical end points is yet to be determined.

High-sensitivity cardiac troponin in stable atherosclerotic vascular disease.

Forward-looking perspective of high-sensitivity cardiac troponin in stable atherosclerotic vascular disease

Impact of the COVID-19 pandemic on the management of risk factors in patients with stable atherosclerotic vascular disease

BackgroundEffective control of risk factors in patients with ASCVD is important to reduce recurrent cardiovascular events. However, many ASCVD patients do not have their risk factors controlled, and this may have worsened during the COVID-19 pandemic. MethodsWe retrospectively evaluated risk factor control among 24,760 ASCVD patients who had at least 1 outpatient encounter both pre-pandemic and during the first year of the pandemic. Risk factors were uncontrolled if the blood pressure (BP) ≥ 130/80 mm Hg, LDL-C ≥ 70 mg/dL, HgbA1c ≥ 7 for diabetic patients, and patients were current smokers. ResultsDuring the pandemic, many patients had their risk factors unmonitored. BP control worsened (BP ≥ 130/80 mmHg, 64.2 vs 65.7%; p = 0.01), while lipid management improved with more patients on a high-intensity statin (38.9 vs 43.9%; p<0.001) and more achieving an LDL-C < 70 mg/dL, less patients were smoking (7.4 vs 6.7%; p<0.001), and diabetic control was unchanged pre vs during the pandemic. Black (OR 1.53 [1.02–2.31]) and younger aged patients (OR 1.008 [1.001–1.015]) were significantly more likely to have missing or uncontrolled risk factors during the pandemic. ConclusionsDuring the pandemic risk factors were more likely to be unmonitored. While measured blood pressure control worsened, lipid control and smoking improved. Although some cardiovascular risk factor control improved during the COVID-19 pandemic, overall control of cardiovascular risk factors in patients with ASCVD was suboptimal, especially in Black and younger patients. This puts many ASCVD patients at increased risk of a recurrent cardiovascular event.

Association Between Achieved Low-Density Lipoprotein Cholesterol Levels and Long-Term Cardiovascular and Safety Outcomes: An Analysis of FOURIER-OLE.

Low-density lipoprotein cholesterol (LDL-C) is a well-established risk factor for atherosclerotic cardiovascular disease. However, the optimal achieved LDL-C level with regard to efficacy and safety in the long term remains unknown. In FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), 27 564 patients with stable atherosclerotic cardiovascular disease were randomized to evolocumab versus placebo, with a median follow-up of 2.2 years. In the open-label extension (FOURIER-OLE), 6635 of these patients were transitioned to open-label evolocumab regardless of initial treatment allocation in the parent trial and were followed for an additional median of 5 years. In this prespecified analysis, we examined the relationship between achieved LDL-C levels (an average of the first 2 LDL-C levels measured) in FOURIER-OLE (available in 6559 patients) and the incidence of subsequent cardiovascular and safety outcomes. We also performed sensitivity analyses evaluating cardiovascular and safety outcomes in the entire FOURIER and FOURIER-OLE patient population. Multivariable modeling was used to adjust for baseline factors associated with achieved LDL-C levels. In FOURIER-OLE, 1604 (24%), 2627 (40%), 1031 (16%), 486 (7%), and 811 (12%) patients achieved LDL-C levels of <20, 20 to <40, 40 to <55, 55 to <70, and ≥70 mg/dL, respectively. There was a monotonic relationship between lower achieved LDL-C levels-down to very low levels <20 mg/dL-and a lower risk of the primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina or coronary revascularization) and the key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) that persisted after multivariable adjustment (adjusted Ptrend<0.0001 for each end points). No statistically significant associations existed in the primary analyses between lower achieved LDL-C levels and increased risk of the safety outcomes (serious adverse events, new or recurrent cancer, cataract-related adverse events, hemorrhagic stroke, new-onset diabetes, neurocognitive adverse events, muscle-related events, or noncardiovascular death). Similar findings were noted in the entire FOURIER and FOURIER-OLE cohort up to a maximum follow-up of 8.6 years. In patients with atherosclerotic cardiovascular disease, long-term achievement of lower LDL-C levels, down to <20 mg/dL (<0.5 mmol/L), was associated with a lower risk of cardiovascular outcomes with no significant safety concerns. URL: https://www. gov; Unique identifier: NCT01764633.

Comparison of Investigator-Reported vs Centrally Adjudicated Major Adverse Cardiac Events

In the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial, there was a significant reduction in the adjudicated primary outcome among patients with stable atherosclerotic vascular disease randomized to dual pathway inhibition (rivaroxaban 2.5 mg twice daily plus aspirin 100 mg daily) vs aspirin monotherapy, but not with rivaroxaban 5 mg twice daily vs aspirin monotherapy. Whether the results are similar without adjudication is unknown. To examine the impact of dual pathway inhibition (with rivaroxaban plus aspirin) or rivaroxaban monotherapy compared with aspirin monotherapy on investigator-reported CV events and to understand the extent of concordance between investigator-reported and centrally adjudicated clinical events. This is a secondary analysis of the COMPASS trial, an international, double-blind, double-dummy, randomized clinical trial with a 3-by-2 partial factorial design that evaluated participants with stable atherosclerotic vascular disease receiving rivaroxaban plus aspirin, rivaroxaban monotherapy, or aspirin monotherapy. End points were collected by blinded site investigators and adjudicated by a blinded clinical end point committee. Data were analyzed from March 2013 through February 2017. Participants received dual inhibition pathway (2.5 mg rivaroxaban twice daily plus 100 mg aspirin once daily), rivaroxaban monotherapy (5 mg twice daily), or aspirin monotherapy (100 mg once daily). The primary efficacy outcome was a composite of cardiovascular (CV) death, stroke, or myocardial infarction (MI). Adjudicated and investigator-reported end points were compared. A total of 27 395 patients (mean [SD] age, 68.2 [7.9] years; 78.0% men) were assessed, including 9152 patients randomized to dual pathway inhibition, 9117 patients randomized to rivaroxaban monotherapy, and 9126 patients randomized to aspirin monotherapy. Adjudication reduced the number of events by 10% to 15% for most end points. Among investigator-reported end points, dual pathway inhibition significantly reduced the rate of the primary efficacy outcome compared with aspirin alone (411 patients [4.5%] vs 542 patients [5.9%]; hazard ratio [HR], 0.75 [95% CI, 0.66-0.85]; P < .001), with similar reduction in adjudicated end points, (379 patients [4.1%] vs 496 patients [5.4%]; HR, 0.76 [95% CI, 0.66-0.86]; P < .001). Likewise, effects on ischemic end points were highly concordant (κ statistic = 0.94 [95% CI, 0.93-0.95] for the primary composite end point). Unlike with adjudicated outcomes, there was a significant reduction in the primary end point with rivaroxaban monotherapy vs aspirin monotherapy using investigator-reported events (477 patients [5.2%] vs 542 patients [5.9%]; HR, 0.88 [95% CI, 0.78-0.99]; P = .04) compared with adjudicated events (448 patients [4.9%] vs 496 patients [5.4%]; HR, 0.90 [95% CI, 0.79-1.03]; P = .12). This secondary analysis of the COMPASS trial found that whether assessed by blinded site investigators or adjudicators, dual pathway inhibition significantly reduced CV events among patients with stable atherosclerotic disease compared with aspirin plus placebo. These findings suggest that using investigator-reported events in blinded clinical trials may be a more efficient alternative to adjudication. ClinicalTrials.gov Identifier: NCT01776424.

Microarray analysis reveals the potential molecular mechanism of Lp299v in stable coronary atherosclerotic disease

A growing body of evidence has confirmed that inflammatory mechanisms are involved in the formation and treatment of coronary atherosclerotic disease (CAD). An increase in circulatory levels of inflammatory cytokines has been found in patients with CAD, while the molecular mechanisms of inflammation still remain elusive. This study was designed to identify differentially expressed genes (DEGs), and to explore the molecular mechanism and hub genes that are involved in the effects of Lactobacillus plantarum 299v (Lp299v) supplementation. Microarray dataset (GSE156357) was downloaded from the Gene Expression Omnibus (GEO) database. The DEGs were identified by the R software. Then, the Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses and construction of protein–protein interaction (PPI) network were performed by DAVID, STRING, and Cytoscape software. In daily alcohol user (DAU) group, 7,541 DEGs were identified, including 206 up-regulated and 7,335 down-regulated DEGs. In non-daily alcohol user (non-DAU) group, 2,799 DEGs were identified (2,491 up-regulated and 308 down-regulated DEGs). The GO enrichment analysis revealed that miosis was up-regulated and immune response was down-regulated. The KEGG enrichment analysis showed that Lp299v supplementation reduced the levels of chemotactic cytokines, and weakened immune response. Proteins of G protein-coupled receptor, inflammatory response, regulation of cell proliferation and apoptosis-related proteins were found in the PPI network. The hub genes were associated with G protein-coupled receptor, inflammatory response, and cell proliferation and apoptosis. The weighted gene co-expression network analysis (WGCNA) enriched the DEGs in 4 modules. This study indicated the expressions of chemokine receptors and regulation of immune response in the Lp299v supplementation. Meanwhile, it was supposed that chemokine receptors may have a cellular effect.

O070 Can the compass trial recommendations be implemented following symptomatic carotid endarterectomy (CEA)?

Abstract Introduction The paradigm changing COMPASS trial (1) demonstrated that in stable atherosclerotic disease, low-dose Rivaroxaban and Aspirin has a significantly greater protective effect on subsequent cardiovascular events (death, stroke or myocardial infarct) than antiplatelet medication alone. This included carotid endarterectomy patients. We assessed our success at implementing COMPASS in our symptomatic CEA patients Methods At the four-week virtual post-CEA review, in suitable patients the general practitioner was advised to change from single antiplatelet to COMPASS regimen. At 6-month follow-up the success and safety of the conversion was assessed. Results For 18 months up to February 2021, 47 patients underwent successful CEA. 29 were recommended for COMPASS, 3 were lost to follow up and 15 were not suitable (6 on DOAC for AF/VTE, 9 complex drug regimen). At 6 months 18 of 29 patients were on the COMPASS regimen (9 not started; 2 withdrawn due to bruising). All patients reported compliance to the regimen. There were no reported haemorrhagic events. 1 patient (not in the COMPASS group) had further multi-territory cerebrovascular events. Conclusion COMPASS is well tolerated in this cohort. Conversion from established drug regimens has yet to gain traction. The benefits on future cardiovascular events post-CEA is yet to be determined. Take-home message Changing post-op medications after a carotid endarterectomy can reduce the later risk of Cardiovascular events. We demonstrate it is possible to successfully do this, but should aim for a higher rate of uptake. (1): N Engl J Med 2017; 377:1319–1330 DOI: 10.1056/NEJMoa1709118

†A Cross-Study Comparison Investigating the Effect of CSL112 (Apolipoprotein A-I [Human]) on Cholesterol Efflux Capacity (Encore ACC 2022)

Lead Author's Financial Disclosures Nothing to disclose. Study Funding CSL Behring, LLC. Background/Synopsis Following an acute myocardial infarction (AMI), patients are at high risk of secondary major adverse cardiovascular events (MACE) that are associated with increased morbidity and mortality. Cholesterol efflux capacity (CEC), a key marker of high- density lipoprotein (HDL) function, is inversely correlated with the incidence of MACE. CSL112 (human-derived apolipoprotein A-I [apoA-I]) is a novel agent in Phase III development, aimed to reduce the risk of MACE following AMI. In Phase I and II clinical trials, CSL112 has demonstrated significant increases in CEC; these studies were conducted across different patient populations, including healthy individuals of different ethnicities known to have variations in lipid metabolism, and have shown CSL112 is well tolerated with a favorable safety profile. Objective/Purpose This cross-study analysis aims to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) properties of CSL112 across prior clinical studies, to assess the impact of ethnicity and disease status on apoA-I exposure and CEC. Methods Data from five CSL112 clinical trials were combined: single and multiple ascending dose Phase I studies in healthy volunteers (N=57 and N=36, respectively), a Phase I Japanese ethno-bridging study (N=52), a Phase IIa study in subjects with stable atherosclerotic disease (N=45), and a Phase IIb study in post-AMI subjects AEGIS-I (N=1267). Dose-normalized and baseline corrected PK parameters and CEC responses were compared between the subpopulations. Results Comparison of PK parameters confirmed that the dose-normalized exposures (measured by the maximum concentration [Cmax] and area under the curve [AUC]) of apoA-I were similar across healthy Caucasian and Japanese subjects, subjects with stable atherosclerosis, and subjects post-AMI. PD parameters were also comparable; dose-normalized baseline-corrected CEC were comparable between Japanese, Caucasian, and post-AMI subjects. In addition, following intravenous infusions of 6 g CSL112, similar fold elevations of apoA-I in Japanese, Caucasian and post-AMI subjects (median 2.08, 2.33, 2.08-fold increase, respectively) and total CEC (median of 2.74, 2.92 and 2.55 fold, respectively) were observed. Conclusions CSL112 induces comparable, immediate and robust increases in key biomarkers across different subpopulations. The comparable distribution range and patterns of CSL112 PK/PD parameters between the subpopulations suggests that disease status or ethnicity do not confer any clinically relevant differences on apoA-I exposure and CEC following CSL112 infusion. These results support the use of a fixed 6g dose in the ongoing global Phase III trial (AEGIS-II), investigating the impact of CSL112 on cardiovascular event risk reduction post- myocardial infarction. Nothing to disclose.

Simultaneous Mass Spectrometry-Based Apolipoprotein Profiling and Apolipoprotein E Phenotyping in Patients with ASCVD and Mild Cognitive Impairment.

Apolipoprotein E (apoE) occurs on the majority of plasma lipoproteins and plays a major role in the lipid metabolism in the periphery and in the central nervous system. ApoE is a polymorphic protein with three common isoforms, apoE2, apoE3 and apoE4, derived from respective alleles ε2, ε3 and ε4. The aim of this study was to develop a sample pretreatment protocol combined with rapid mass spectrometry (MS)-based assay for simultaneous apolipoprotein profiling and apoE phenotype identification. This assay was validated in 481 samples from patients with stable atherosclerotic cardiovascular disease (ASCVD) and applied to study association with mild cognitive impairment (MCI) in the LIFE Adult study, including overall 690 study subjects. Simultaneous quantification of 8–12 major apolipoproteins including apoA-I, apoB-100 and apoE could be performed within 6.5 min. Phenotyping determined with the developed MS assay had good agreement with the genotyping by real-time fluorescence PCR (97.5%). ApoE2 isoform was associated with the highest total apoE concentration compared to apoE3 and apoE4 (p < 0.001). In the subgroup of diabetic atherosclerotic cardiovascular disease (ASCVD) patients, apoE2 isoform was related to higher apoC-I levels (apoE2 vs. apoE3, p < 0.05), while in the subgroup of ASCVD patients under statin therapy apoE2 was related to lower apoB-100 levels (apoE2 vs. apoE3/apoE4, p < 0.05). A significant difference in apoE concentration observed between mild cognitive impairment (MCI) subjects and controls was confirmed for each apoE phenotype. In conclusion, this study provides evidence for the successful implementation of an MS-based apoE phenotyping assay, which can be used to assess phenotype effects on plasma lipid and apolipoprotein levels.

Efficacy and Safety Considerations With Dose-Reduced Direct Oral Anticoagulants

ImportanceDose-reduced regimens of direct oral anticoagulants (DOACs) may be used for 2 main purposes: dose-adjusted treatment intended as full-intensity anticoagulation (eg, for stroke prevention in atrial fibrillation [AF] in patients requiring dose reduction) or low-intensity treatment (eg, extended-duration treatment of venous thromboembolism [VTE]). We reviewed randomized clinical trials (RCTs) to understand the scenarios in which dose-adjusted or low-intensity DOACs were tested and reviewed the labeled indications by regulatory authorities, using data from large registries to assess whether the use of dose-reduced DOACs in routine practice aligned with the findings of RCTs.ObservationsAmong 4191 screened publications, 35 RCTs that used dose-adjusted DOACs were identified for dabigatran, apixaban, rivaroxaban, and edoxaban. Of these 35 RCTs, 29 were related to stroke prevention in AF. Efficacy and safety results for dose-adjusted DOACs in large RCTs of AF were similar to those found for full-dose DOACs. To our knowledge, dabigatran, apixaban, and rivaroxaban have not been studied as dose-adjusted therapy for acute VTE treatment. Low-intensity DOACs were identified in 37 RCTs. Low-intensity DOACs may be used for extended-duration treatment of VTE (apixaban and rivaroxaban), primary prevention in orthopedic surgeries (dabigatran, apixaban, and rivaroxaban), primary prevention in ambulatory high-risk cancer patients (apixaban and rivaroxaban) or (postdischarge) high-risk medical patients (rivaroxaban), in stable atherosclerotic vascular disease, or after a recent revascularization for peripheral artery disease in conjunction with aspirin (rivaroxaban). Minor variations exist between regulatory authorities in different regions regarding criteria for dose adjustment of DOACs. Data from large registries indicated that dose-reduced DOACs were used occasionally with doses or for clinical scenarios different from those studied in RCTs or recommended by regulatory authorities.Conclusions and RelevanceDose adjustment and low-intensity treatment are 2 different forms of dose-reduced DOACs. Dose adjustment is mostly relevant for AF and should be done based on the approved criteria. Dose adjustment of DOACs should not be used for acute VTE treatment in most cases. In contrast, low-intensity DOACs may be used for primary or secondary VTE prevention for studied and approved indications. Attention should be given to routine practice patterns to align the daily clinical practice with existing evidence of safety and efficacy.

Early Initiation of Evolocumab Treatment in Chinese Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention

Evolocumab has been shown to improve cardiovascular outcomes in patients with stable atherosclerotic disease. Whether this benefit persists in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) remains undetermined. This study aimed to evaluate the efficacy and safety of the early initiation of evolocumab in Chinese patients with ACS undergoing PCI. This retrospective cohort study involved 1564 consecutive patients who had been hospitalized with ACS and underwent PCI, and who had elevated LDL-C levels (≥1.8 mmol/L after receiving high-intensity statin therapy for ≥4 weeks; ≥2.3 mmol/L after receiving low- or moderate-intensity statin; or ≥3.2 mmol/L without statin therapy). Patients who received evolocumab (initiated in-hospital and after 18 months) were included in the evolocumab group (n=414), and all other patients were included in the control group (n=1150). The primary outcome at 18 months was a composite of ischemic stroke, cardiovascular death, myocardial infarction, hospitalization for unstable angina, or coronary revascularization. The evolocumab treatment effect on the primary outcome was assessed in all prespecified subgroups. At 18 months, evolocumab combined with statins reduced LDL-C levels from baseline levels by 42.48% compared with statins alone. After multivariable adjustment, evolocumab combined with statins significantly reduced the primary outcome (8.2% vs 12.4%; adjusted hazard ratio, 0.65; 95% CI, 0.45-0.95; P=0.025). In addition, evolocumab consistently reduced the primary outcome across the major subgroups. For the safety outcomes, no significant differences between the groups were observed in any adverse events. Among Chinese patients who underwent PCI for ACS, the early initiation of evolocumab combined with statin treatment effectively reduced LDL-C levels and lowered the incidence of recurrent ischemic cardiovascular events, with satisfactory tolerability and safety. Chinese Clinical Trial Registry identifier: ChiCTR2100049364.

No association between APOE genotype and lipid lowering with cognitive function in a randomized controlled trial of evolocumab.

APOE encodes a cholesterol transporter, and the ε4 allele is associated with higher circulating cholesterol levels, ß-amyloid burden, and risk of Alzheimer’s disease. Prior studies demonstrated no significant differences in objective or subjective cognitive function for patients receiving the PCSK9 inhibitor evolocumab vs. placebo added to statin therapy. There is some evidence that cholesterol-lowering medications may confer greater cognitive benefits in APOE ε4 carriers. Thus, the purpose of this study was to determine whether APOE genotype moderates the relationships between evolocumab use and cognitive function. APOE-genotyped patients (N = 13,481; 28% ε4 carriers) from FOURIER, a randomized, placebo-controlled trial of evolocumab added to statin therapy in patients with stable atherosclerotic cardiovascular disease followed for a median of 2.2 years, completed the Everyday Cognition Scale (ECog) to self-report cognitive changes from the end of the trial compared to its beginning; a subset (N = 835) underwent objective cognitive testing using the Cambridge Neuropsychological Test Automated Battery as part of the EBBINGHAUS trial. There was a dose-dependent relationship between APOE ε4 genotype and patient-reported memory decline on the ECog in the placebo arm (p = .003 for trend across genotypes; ε4/ε4 carriers vs. non-carriers: OR = 1.46, 95% CI [1.03, 2.08]) but not in the evolocumab arm (p = .50, OR = 1.18, 95% CI [.83,1.66]). However, the genotype by treatment interaction was not significant (p = .30). In the subset of participants who underwent objective cognitive testing with the CANTAB, APOE genotype did not significantly modify the relationship between treatment arm and CANTAB performance after adjustment for demographic and medical covariates, (p’s>.05). Although analyses were limited by the low population frequency of the ε4/ε4 genotype, this supports the cognitive safety of evolocumab among ε4 carriers, guiding future research on possible benefits of cholesterol-lowering medications in people at genetic risk for Alzheimer’s disease.

Platelet P2Y12 inhibiting therapy in adjunct to vascular dose of rivaroxaban or aspirin: a pharmacodynamic study of dual pathway inhibition vs. dual antiplatelet therapy.

Dual pathway inhibition (DPI) by adding a vascular dose of rivaroxaban to a single antiplatelet agent has emerged as a promising antithrombotic strategy. However, in most studies the antiplatelet agent of choice used in adjunct to a vascular dose of rivaroxaban was aspirin, and data on a P2Y12 inhibitor and how this DPI regimen compares with standard dual antiplatelet therapy (DAPT) are limited. This investigation was a substudy analysis conducted in selected cohorts of patients with stable atherosclerotic disease enrolled from a larger prospective, open-label, parallel-group pharmacodynamic (PD) study. We analysed data from 40 patients treated with either clopidogrel- or ticagrelor-based DAPT first, and clopidogrel- or ticagrelor-based DPI thereafter. PD measures explored key pathways involved in thrombus formation and included markers of (1) P2Y12 reactivity, (2) platelet-mediated global thrombogenicity, (3) cyclooxygenase-1 activity, (4) thrombin receptor-activating peptide (TRAP)-induced platelet aggregation, (5) tissue factor (TF)-induced platelet aggregation, and (6) thrombin generation. Compared with DAPT, on a background of the same P2Y12 inhibitor (clopidogrel or ticagrelor), DPI was associated with reduced thrombin generation, increased markers of cyclooxygenase-1 activity and TRAP-induced platelet aggregation, and no differences in markers of P2Y12 signalling, platelet-mediated global thrombogenicity, and TF-induced platelet aggregation. In an analysis according to P2Y12 inhibitor type, ticagrelor reduced markers of platelet-mediated global thrombogenicity, P2Y12 signalling, and rates of high platelet reactivity compared with clopidogrel. Compared with DAPT with aspirin and a P2Y12 inhibitor, the use of a P2Y12 inhibitor in adjunct to a vascular dose of rivaroxaban as part of a DPI strategy is associated with similar effects on platelet-mediated global thrombogenicity but reduced thrombin generation. A DPI strategy with ticagrelor is associated with enhanced antithrombotic efficacy, the clinical implications of which warrant larger scale investigations. ClinicalTrials.gov identifier: NCT03718429.

Effect of Evolocumab in Patients With Prior Percutaneous Coronary Intervention.

Patients with prior percutaneous coronary intervention (PCI) are at high residual risk for multiple types of coronary events within and beyond the stented lesion. This risk might be mitigated by more intensive LDL-C (low-density lipoprotein cholesterol)-lowering beyond just with statin therapy. FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) randomized 27 564 patients with stable atherosclerotic disease on statin to the PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitor evolocumab or placebo with a median follow-up of 2.2 years. The end points of interest were major adverse cardiovascular events (MACE; a composite of cardiovascular death, myocardial infarction, stroke, unstable angina or coronary revascularization), and major coronary events (a composite of coronary heart death, myocardial infarction, or coronary revascularization). We compared the risk of MACE and the magnitude of relative and absolute risk reductions with evolocumab in patients with and without prior PCI. Seventeen thousand seventy-three patients had prior PCI. In the placebo arm, those with prior PCI had higher rates of MACE (13.2% versus 8.3%; hazard ratio [HR]adj 1.61 [95% CI, 1.42-1.84]; P<0.0001) and major coronary events (11.5% versus 6.0%; HRadj, 1.72 [95% CI, 1.49-1.99]; P<0.0001). Relative risk reductions with evolocumab were similar in patients with and without prior PCI (MACE: HR, 0.84 [0.77-0.91] versus HR, 0.88 [0.77-1.01]; Pinteraction 0.51; major coronary events: HR, 0.82 [0.75-0.90] versus HR, 0.88 [0.75-1.04]; Pinteraction 0.42). Absolute risk reductions for MACE were 2.0% versus 0.9% (Pinteraction 0.14) and for major coronary events 2.0% versus 0.7% (Pinteraction 0.045). In those with prior PCI, the effect of evolocumab on coronary revascularization (HR, 0.76 [0.69-0.85]) was directionally consistent across types of revascularization procedures: coronary artery bypass grafting (HR, 0.71 [0.54-0.94]); any PCI (HR, 0.77 [0.69-0.86]); PCI for de novo lesions (HR, 0.76 [0.66-0.88]); and PCI for stent failure or graft lesions (HR, 0.76 [0.63-0.91]). Evolocumab reduces the risk of MACE in patients with prior PCI including the risk of coronary revascularization, with directionally consistent effects across several types of revascularization procedures, including coronary artery bypass grafting and PCI for stent or graft failure. URL: https://www. gov; Unique identifier: NCT01764633.

Pharmacodynamic Profiles of Dual-Pathway Inhibition with or without Clopidogrel versus Dual Antiplatelet Therapy in Patients with Atherosclerotic Disease

Inhibition of thrombin-mediated signaling processes using a vascular dose of rivaroxaban in adjunct to antiplatelet therapy, known as dual-pathway inhibition (DPI), reduces atherothrombotic events in patients with stable atherosclerotic disease. However, there are limited data on the pharmacodynamic (PD) effects of this strategy and how it compares to standard dual antiplatelet therapy (DAPT). This investigation was conducted in selected cohorts of patients (n = 40) with stable atherosclerotic disease-enrolled within a larger prospective, open-label, parallel-group PD study-who were treated with either aspirin plus clopidogrel (DAPT), aspirin plus rivaroxaban 2.5 mg/bid (DPI), or DAPT plus rivaroxaban 2.5 mg/bid. Multiple PD assays providing a comprehensive assessment of markers of thrombosis were used. PD endpoints included platelet-mediated global thrombogenicity measured by light transmittance aggregometry (LTA) following stimuli with CATF (collagen-related peptide + adenosine diphosphate [ADP] + tissue factor [TF]), markers of P2Y12 reactivity, markers of platelet aggregation using LTA following several stimuli (arachidonic acid, ADP, collagen, TF, and thrombin receptor-activating peptide [TRAP]), thrombin generation, and thrombus formation. There was no difference in platelet-mediated global thrombogenicity between groups. Rivaroxaban significantly reduced thrombin generation and was associated with a trend toward reduced TF-induced platelet aggregation. Clopidogrel-based treatments reduced markers of P2Y12 signaling and TRAP-induced platelet aggregation. There were no differences between groups on markers of cyclooxygenase-1-mediated activity. Compared with DAPT, DPI does not result in any differences in platelet-mediated global thrombogenicity, but reduces thrombin generation. These PD observations suggest that modulating thrombin generation-by means of factor Xa inhibition-in adjunct to antiplatelet therapy provides effective antithrombotic effects, supporting the efficacy and safety findings of a DPI strategy observed in clinical trials.