Secondary Prevention Settings Research Articles

Abstract 4122948: Lipoprotein(a) associated risk of atherosclerotic cardiovascular disease is independent of C-reactive protein

Background: Elevated lipoprotein(a), present in 1 in 5 individuals, is considered a causal risk factor for atherosclerotic cardiovascular disease (ASCVD). Recent studies have reached contrasting conclusions on whether low-grade inflammation measured by elevated C-reactive protein (CRP) modifies the risk of ASCVD from high lipoprotein(a). We tested the hypothesis that high lipoprotein(a) associates with risk of recurrent ASCVD irrespective of elevated or low CRP. Additionally, we performed meta-analyses of previous studies on lipoprotein(a)-associated ASCVD risk stratified by CRP levels and by incident or recurrent events. Methods: We included 3,543 individuals with prevalent ASCVD from the Copenhagen General Population Study (CGPS), a contemporary, prospective Danish cohort study. Hazard ratios (HR) for ASCVD were examined using multivariable adjusted Cox regressions stratified by CRP (<2 mg/L and ≥2 mg/L). Random-effects meta-analyses in primary (incident events) and secondary (recurrent events) prevention were conducted separately, including studies on lipoprotein(a) and risk of ASCVD stratified by CRP. Results: During a median of 7.5 years of follow-up of 3,543 CGPS participants with established ASCVD, 1,425 experienced a recurrent ASCVD event. Multivariable adjusted HRs for ASCVD for high vs. low lipoprotein(a) were 1.41 (95% confidence interval: 1.19-1.67) and 1.31 (1.08-1.59) in individuals with low or elevated CRP with no evidence of effect modification (Figure 1A, p for interaction=0.11). When risk estimates for ASCVD were summarized in separate meta-analyses for primary and secondary prevention settings, a 50 mg/dL higher lipoprotein(a) was robustly associated with increased risk of ASCVD irrespective of CRP levels (Figure 1B). In primary prevention, a 50 mg/dL higher lipoprotein(a) associated with similar summary HRs of 1.18 (1.15-1.20) in low CRP vs. 1.16 (1.14-1.19) in elevated CRP, and likewise in secondary prevention settings, with similar HRs of 1.10 (1.07-1.14) and 1.14 (1.10-1.17), respectively. Conclusion: High lipoprotein(a) was associated with increased risk of ASCVD irrespective of CRP levels both in primary and secondary prevention settings.

Abstract 4137922: Cardiovascular Prognosis of Statin Users Developing Diabetes in Secondary Prevention: A Prospective Multicenter Study

Background: In primary prevention, statin use with new-onset diabetes mellitus (DM) was associated with increased atherosclerotic cardiovascular disease (ASCVD) risk. In high-risk and secondary prevention settings, the cardiovascular prognosis of statin users progressing to new-onset DM remains unclear. Methods: We collected data from inpatients with or without baseline ASCVD from four medical centers affiliated to Qingdao University. Patients were categorized into 4 phenotypes: (1) statin non-users without diabetes; (2) statin users with incident diabetes; (3) statin users with pre-existing diabetes; and (4) statin users without diabetes. The primary outcome was ASCVD events. The stratified Cox proportional hazard model was used to investigate the association between the four distinct phenotypes and the risk of ASCVD. Results: Among 12,800 high-risk patients, over a median follow-up of 118 days (interquartile range, 48-379 days), 1447 ASCVD events were documented. Compared with statin non-users without diabetes, statin users without diabetes (hazard ratio [95% confidence interval], 0.77 [0.65, 0.91], P=0.001) and statin users with pre-existing diabetes (0.80 [0.66, 0.99], P=0.035) were associated with lower risk of ASCVD, whereas statin users with new-onset diabetes were not (0.91 [0.70, 1.19], P=0.50), overall P for trend =0.013.( Figure 1 ) In patients with baseline ASCVD (i.e., secondary prevention settings), we observed similar findings ( Figure 2 ) Conclusions: In high-risk patients with pre-existing ASCVD, new-onset diabetes after statin use was likely associated with compromised cardiovascular benefits of statins.

Circulating Amyloid beta 1-40 is independently associated with statin treatment and LDL cholesterol reduction: a prospective cohort study

Abstract Background Accumulating evidence suggests that circulating amyloid beta 1-40 (Aβ40), a pro-inflammatory and pro-atherogenic peptide, is associated with atherosclerotic cardiovascular disease (ASCVD), providing incremental prognostic value and risk stratification refinement in primary and secondary prevention settings. Existing evidence supports conflicting off-target effects of statins on plasma Aβ40. We aim to explore the impact of cardiovascular risk reduction through statin therapy on Aβ40 plasma levels in subjects with dyslipidemia and with/without ASCVD. Methods In this prospective study, patients with dyslipidemia who visited for the first time our lipid clinic for risk stratification and treatment plan assessment (n=146) were consecutively recruited. Αβ40 was measured in plasma samples by enzyme-linked immunosorbent assay at baseline and after a mean follow-up of 5.2 and 15 months. Patients in whom statin treatment was initiated or intensified in terms of dose or regimen (n= 68) were compared against patients not treated with statins or with unchanged statin intensity (n = 78). Statin intensity treatment was defined based on the European Society of Cardiology (ESC) guidelines. Results Increased Aβ40 plasma levels at baseline were associated with ASCVD presence, decreased glomerular filtration rate (GFR), and history of heart failure (p<0.05 for all). An increase in Aβ40 circulating levels between baseline and follow-up 1 was observed in patients in whom statin treatment was initiated or intensified (p=0.041). However, in patients not treated with statins or treated with unchanged statin intensity, an increase in Aβ40 circulating levels was observed between follow-up 1 and follow-up 2 (p=0.05, Figure 1A). These changes in Aβ40 were significantly different between the two groups during the short follow-up period (β=0.226, p for interaction =0.025) independently from age and changes in GFR, systolic blood pressure, and LDL-C. Additionally, patients who achieved a reduction in low-density lipoprotein cholesterol (LDL-C) ≥ 50% in follow-up 2 have unchanged Aβ40 levels during the long follow-up period, while an increase in Aβ40 was observed in the rest population (p=0.012, Figure 1B). These changes were significantly different between the two LDL-C groups independently of statin treatment and changes in high sensitive C-reactive protein (hs-CRP) (β= -0.231, p for interaction=0.035). Conclusion In a dyslipidemic population, statin initiation or intensification and LDL-C decrease showed a short-term increase and a long-term return to initial levels, respectively, in circulating Aβ40 levels. From a mechanistic point of view, our findings suggest that statins have an impact on Aβ40, possibly through an LDL-C-dependent and a non-LDL-C-dependent pathway. Further studies are needed to evaluate the utility of circulating Aβ40 as a novel biomarker in ASCVD risk reduction assessment.

The association of inflammation, triglycerides and lipoprotein(a) with cardiovascular events in the UK Biobank

Abstract Background Recent trial data has suggested that high-sensitivity C-reactive protein (hsCRP) is, at least, as strong a predictor of future cardiovascular events as LDL cholesterol in patients on lipid-lowering therapy1,2. There are limited data however on how hsCRP and other additional risk factors perform in patients at different levels of CVD risk. Purpose To evaluate the relationship of hsCRP, triglyceride and lipoprotein(a) [Lp(a)] levels with cardiovascular events in guideline-defined, clinically distinct cohorts. Such a study will improve the understanding of CVD risk prediction and provide essential information on the role of these pathways in CVD. Methods Data from the UK Biobank were used. In accordance with the 2021 ESC CVD prevention guidelines, four risk groups were derived based on clinical data and 10-year CVD risk, calculated from the recently derived SCORE2 model (Figure 1)3. Those not falling into one of the four cohorts were excluded as further risk stratification in these individuals would not influence management. For increasing quartiles (Q) of each biomarker, hazard ratios (HR), 95% confidence intervals (CI) and p-values were calculated relative to the lowest Q, using Cox proportional hazards models, adjusted for age, sex, smoking status, systolic blood pressure, HDL cholesterol and total cholesterol. Interactions between sex and biomarker were explored. The primary endpoint was major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death, myocardial infarction, and ischaemic stroke. Secondary endpoints were the individual components of the primary endpoint. Results A total of 229,339 participants were included across the four risk groups, with a total of 24,133 primary endpoint events over the mean follow-up period of 14 years. In all four groups there was a robust linear relationship of hsCRP with MACE (p<0.001 [Figure2]) – strongest in the secondary prevention population (Q4 v Q1 HR=1.79 [95%CI:1.60, 2.02]). Of the secondary endpoints, hsCRP was most strongly associated with cardiovascular death (Q4 v Q1 secondary prevention cohort HR=1.97 [1.68, 2.30]). Lp(a) was associated with MACE in the primary prevention cohorts only (Q4 vs Q1 high-risk cohort HR=1.35 [1.27, 1.44]), driven by its strong association with myocardial infarction (Q4 vs Q1 HR 1.61 [1.48, 1.75]) but not other secondary endpoints. After adjustment, triglyceride levels were not associated with MACE in the four cohorts. There was no evidence of sex interactions in any analysis (p>0.05). Conclusions After adjustment for traditional CVD risk factors, hsCRP is a more robust predictor of cardiovascular events than Lp(a) or triglycerides in both primary and secondary prevention settings. Consideration should be given to evaluating whether hsCRP, Lp(a) and other ‘non-traditional’ risk factors can improve CVD risk reclassification and/or be used to guide allocation to targeted anti-atherosclerotic therapies.Figure 1:Participant FlowFigure 2:Main effects

Impact of the severe familial hypercholesterolemia status on atherosclerotic risks

Abstract Backgrounds Risks of atherosclerotic events substantially vary even among patients with familial hypercholesterolemia (FH) with extremely high risk based on life-long exposure to high low-density lipoprotein cholesterol levels. Purpose This study aimed to examine the impact of the severe FH status defined by the International Atherosclerosis Society (IAS). Methods Data of patients with FH (N = 1,050, male = 490) who were admitted to our university hospital between 2000 and 2020 and who were followed up were retrospectively reviewed. The number of major adverse cardiac events (MACEs), including mortality associated with cardiovascular disease, acute coronary syndrome, and ischemic heart disease requiring coronary revascularization per 1,000 person-years, was calculated. Hazard ratio was also calculated using Cox proportional model. Results Overall, 545 (51.9%) patients had severe FH. The median follow-up duration was 12.6 years. In total, 171 MACEs were recorded during the follow-up period. Severe FH was significantly associated with MACE (hazard ratio = 6.48, 95% confidence interval = 2.56–10.40, P < 0.001). The event rates per 1,000 person-years in the primary prevention group of non-severe FH and severe FH, were 0.0 and 15.6, respectively. The event rates per 1,000 person-years in the secondary prevention group of non-severe FH and severe FH, were 2.0 and 32.3, respectively. Conclusions Patients with severe FH exhibited significantly higher risks in primary and secondary prevention settings. This simple criterion provides useful information for identifying patients with even higher risk who may need further management.

Major Adverse Cardiovascular Events Following Coronary Artery Stenting by History of Hypertensive Disorder of Pregnancy.

A history of hypertensive disorders of pregnancy is associated with at least twice the risk of incident ischemic heart disease. Whether the long-term outcome following treatment with coronary artery stenting is associated to the history of hypertensive disorders of pregnancy is unknown. We included 8364 women (age ≤65 years) undergoing first coronary artery stenting 2006 to 2022 following their first delivery in 1973 or later, linking nationwide data on percutaneous coronary intervention and delivery history. In total, 1122 women (13.4%) had a history of hypertensive disorders of pregnancy. The main outcome, a major adverse cardiovascular event, was defined as any incident myocardial infarction, ischemic heart disease, cardiac arrest, arrhythmias, angina pectoris, heart failure, cerebral infarction, or sudden death. During a median follow-up time of 5 years, 258 women with a history of hypertensive disorders of pregnancy had a major adverse cardiovascular event, compared with 1465 women without a history of hypertensive disorders of pregnancy (23% versus 20.2%, P=0.028 for log-rank test). Estimates adjusted for patient- and procedural characteristics in proportional hazards regression models suggested that the hazard rate increased only after 4-8 years of follow-up (hazard ratio [HR], 1.36 [95% CI, 1.05-1.78]) and was primarily driven by women with history of gestational hypertension (HR, 2.15 [95% CI, 1.49-3.11]). Women with a history of hypertensive disorders of pregnancy have an increased risk of a major adverse cardiovascular event following coronary artery stenting compared with other parous women. A history of hypertensive disorders of pregnancy warrants further attention in the secondary prevention setting of coronary artery disease.

Effect of nuts on lipid profile and inflammatory biomarkers in atherosclerotic cardiovascular disease: a systematic review and meta-analysis of randomized controlled trials.

Nut-enriched diets are related to improve lipid and inflammatory biomarkers in meta-analyses in the context of primary cardiovascular prevention. However, primary studies on secondary cardiovascular prevention are scarce and controversial. This systematic review and meta-analysis aimed to evaluate the effect of nut supplementation on lipid and inflammatory profiles in individuals with atherosclerotic cardiovascular disease, and the frequency of adverse events. Six databases were used for research: PubMed, EMBASE, BVS, Cochrane Library, Web of Science, and ClinicalTrials.gov, until February 2023, with no language restrictions. We performed random-effects meta-analyses to compare nut-enriched diets vs. control diets for pre-post intervention changes. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system assessed the evidence's certainty. From the 5187 records identified, eight publications containing data referring to five randomized clinical trials involving 439 participants were included in the final analyses. The nuts evaluated were almonds, pecans, Brazil nuts, and mixed nuts, with doses ranging between 5g and 85g (median: 30g/day). The intervention time varied between 6 and 12 weeks. Compared to nut-free diets, nut intake did not have a statistically significant effect on lipid profile biomarkers, except on the atherogenic index (MD: -0.32 [95% CI -0.58 to -0.06], I2 = 0% - moderate certainty of the evidence). Similarly, there was no effect of nuts on inflammatory profile biomarkers. It was not possible to aggregate data on adverse events. Nut supplementation did not change lipid and inflammatory profiles in the secondary cardiovascular prevention setting.

Estimated glomerular filtration rate slope and risk of primary and secondary major adverse cardiovascular events and heart failure hospitalization in people with type 2 diabetes: An analysis of the EXSCEL trial.

The decline in estimated glomerular filtration rate (eGFR), a significant predictor of cardiovascular disease (CVD), occurs heterogeneously in people with diabetes because of various risk factors. We investigated the role of eGFR decline in predicting CVD events in people with type 2 diabetes in both primary and secondary CVD prevention settings. Bayesian joint modelling of repeated measures of eGFR and time to CVD event was applied to the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial to examine the association between the eGFR slope and the incidence of major adverse CV event/hospitalization for heart failure (MACE/hHF) (non-fatal myocardial infarction, non-fatal stroke, CV death, or hospitalization for heart failure). The analysis was adjusted for age, sex, smoking, systolic blood pressure, baseline eGFR, antihypertensive and lipid-lowering medication, diabetes duration, atrial fibrillation, high-density cholesterol, total cholesterol, HbA1c and treatment allocation (once-weekly exenatide or placebo). Data from 11 101 trial participants with (n = 7942) and without (n = 3159) previous history of CVD were analysed. The mean ± SD eGFR slope per year in participants without and with previous CVD was -0.68 ± 1.67 and -1.03 ± 2.13 mL/min/1.73 m2, respectively. The 5-year MACE/hHF incidences were 7.5% (95% CI 6.2, 8.8) and 20% (95% CI 19, 22), respectively. The 1-SD decrease in the eGFR slope was associated with increased MACE/hHF risks of 48% (HR 1.48, 95% CI 1.12, 1.98, p = 0.007) and 33% (HR 1.33, 95% CI 1.18,1.51, p < 0.001) in participants without and with previous CVD, respectively. eGFR trajectories over time significantly predict incident MACE/hHF events in people with type 2 diabetes with and without existing CVD, with a higher hazard ratio for MACE/hHF in the latter group.

Investigating the causal effect of previously reported therapeutic agents for colorectal cancer prevention: protocol for a Mendelian randomization analysis.

Colorectal cancer (CRC) is the third most common cancer worldwide, with 1.9 million new cases in 2020 and a predicted rise to 3.2 million in 2040. Screening programmes are already in place to aid early detection and secondary prevention of CRC, but the rising prevalence means additional approaches are required in both primary and secondary prevention settings. Preventive therapy, whereby natural or synthetic agents are used to prevent, reverse or delay disease development, could be an effective strategy to further reduce cancer risk and potential agents have already been identified in conventional observational studies. However, as such studies are vulnerable to confounding and reverse causation, we aim to evaluate these observed relationships using Mendelian randomization (MR), an alternative causal inference approach which should be less susceptible to these biases. We will use two-sample MR, which uses two independent samples for the exposure and outcome data, to investigate previously reported observational associations of multiple potential preventive agents with CRC risk. We define preventive agents as any synthetic (e.g. approved medication) or natural (e.g. micronutrient, endogenous hormone) molecule used to reduce the risk of cancer. We will first extract potential preventive agents that have been previously linked to CRC risk in observational studies from reviews of the literature. We will then evaluate whether we can develop a genetic instrument for each preventive agent from previously published genome-wide association studies (GWASs) of direct measures of molecular traits (e.g. circulating levels of protein drug targets, blood-based biomarkers of dietary vitamins). The summary statistics from these GWASs, and a large GWAS of CRC, will be used in two-sample MR analyses to investigate the causal effect of putative preventive therapy agents on CRC risk. Sensitivity analyses will be conducted to evaluate the robustness of findings to potential violations of MR assumptions.

Differential effects of cigarette smoking on cardiovascular disease in females: A narrative review and call to action

ObjectiveCigarette smoking continues to be a major driver in the incidence and progression of cardiovascular disease (CVD). As females become an increasingly larger fraction of those who smoke it is imperative that the sex-specific effects of smoking be further explored and acted upon. MethodsThis narrative review describes current evidence on the differential effects of smoking on CVD in females and the need to improve treatment. ResultsEvidence to date suggests that smoking has disproportionately negative effects on the cardiovascular (CV) system in females, especially in those who are younger. Usually, the onset of CVD is later in females than males, but smoking decreases or eliminates this gap. Females are also more likely to develop types of CVD closely tied to smoking, such as ST-elevated myocardial infarctions, with even higher rates among those who are younger. Possible mechanisms for these worse outcomes in females include a complex interplay between nicotine, other products of combusted cigarettes, and hormones. Sex differences also exist in treatment for smoking. In females, Varenicline appears more effective than either Bupropion or nicotine replacement therapy while in males, all three therapies show similar efficacy. Disparities in smoking are also apparent in secondary prevention settings. Females and males are entering secondary prevention with equal rates of smoking, with potentially higher levels of exposure to the byproducts of smoking in females. ConclusionsThese disproportionately negative outcomes for females who smoke require additional research and these persisting rates of smoking suggest a need for female-specific approaches for treating smoking.

Effect of bempedoic acid on mortality and cardiovascular events in primary and secondary prevention: A post-hoc analysis of the CLEAR-outcomes trial

BackgroundThe effects of bempedoic acid on mortality in the secondary prevention setting have not been examined. MethodsWe used data from the overall and primary prevention reports of CLEAR – Outcomes to reconstruct data for the secondary prevention population. A Bayesian analyses was employed to calculate the posterior probability of benefit or harm for the outcomes of all-cause mortality, cardiovascular mortality, and major adverse cardiovascular events (MACE). Relative effect sizes are presented as risk ratios (RR) with 95% credible intervals (CrI), which represent the intervals that true effect sizes are expected to fall in with 95% probability, given the priors and model. ResultsIn primary prevention, the posterior probability of bempedoic acid decreasing all-cause and cardiovascular mortality was 99.4% (RR: 0.70; 95% CrI: 0.51 to 0.92) and 99.7% (RR: 0.58; 95% CrI: 0.38 to 0.86) respectively. In secondary prevention, the posterior probability of bempedoic acid increasing all-cause and cardiovascular mortality was 96.6% (RR: 1.15; 95% CrI: 0.99 to 1.33) and 97.2% (RR: 1.21; 95% CrI: 1.00 to 1.45) respectively. The probability of bemepdoic acid reducing MACE in the primary and secondary prevention settings was 99.9% (RR: 0.70; 95% CrI: 0.54 to 0.88) and 95.8% (RR: 0.92; 95% CrI: 0.84 to 1.01) respectively. ConclusionIn contrast to its effect in the primary prevention subgroup of CLEAR – Outcomes, bempedoic acid resulted in a more modest MACE reduction and a potential increase in mortality in the secondary prevention subgroup. Whether these findings represent true treatment effect heterogeneity or the play of chance requires further evidence.

Investigating the causal effect of previously reported therapeutic agents for colorectal cancer prevention: protocol for a Mendelian randomization analysis

Background Colorectal cancer (CRC) is the third most common cancer worldwide, with 1.9 million new cases in 2020 and a predicted rise to 3.2 million in 2040. Screening programmes are already in place to aid early detection and secondary prevention of CRC, but the rising prevalence means additional approaches are required in both primary and secondary prevention settings. Preventive therapy, whereby natural or synthetic agents are used to prevent, reverse or delay disease development, could be an effective strategy to further reduce cancer risk and potential agents have already been identified in conventional observational studies. However, as such studies are vulnerable to confounding and reverse causation, we aim to evaluate these observed relationships using Mendelian randomization (MR), an alternative causal inference approach which should be less susceptible to these biases. Methods and analysis We will use two-sample MR, which uses two independent samples for the exposure and outcome data, to investigate previously reported observational associations of multiple potential preventive agents with CRC risk. We define preventive agents as any synthetic (e.g. approved medication) or natural (e.g. micronutrient, endogenous hormone) molecule used to reduce the risk of cancer. We will first extract potential preventive agents that have been previously linked to CRC risk in observational studies from reviews of the literature. We will then evaluate whether we can develop a genetic instrument for each preventive agent from previously published genome-wide association studies (GWASs) of direct measures of molecular traits (e.g. circulating levels of protein drug targets, blood-based biomarkers of dietary vitamins). The summary statistics from these GWASs, and a large GWAS of CRC, will be used in two-sample MR analyses to investigate the causal effect of putative preventive therapy agents on CRC risk. Sensitivity analyses will be conducted to evaluate the robustness of findings to potential violations of MR assumptions.

#366 : Adjuvants to Prevent Reformation of Adhesions Following Adhesiolysis for Asherman Syndrome

Background and aims: Two international guidelines published on the management of Asherman syndrome (AS) have made recommendations on various adjuvant methods to prevent intrauterine reformation. Nevertheless, the effectiveness of these methods when used in primary or secondary prevention settings is different. Our aim is to assess the effectiveness of various adjuvant methods for the secondary prevention of intrauterine adhesions (IUAs). Methods: Articles were considered eligible if they included subjects with AS before surgery and compared a chosen method with either a control or a comparison group (using another method). The primary outcome was IUA reformation rate at follow-up hysteroscopy. Results: A total of 29 studies [15 randomised controlled trial (RCTs)] and 14 cohort studies) were included. Adhesion reformation with various methods to prevented IUA reformation when compared with controls were: second-look hysteroscopy:[risk ratio(RR) 0.21, 95% confidence interval (CI) 0.05 to 0.90 (P=0.02)];intrauterine contraceptive device: RR: 0.64, 95% CI: 0.36 to 1.12 (P=0.12);continuous intrauterine balloon: RR: 0.18, 95% CI: 0.05 to 0.68 (P=0.01);intermittent intrauterine balloon: RR: 0.50, 95% CI: 0.31 to 0.80 (P=0.004);anti-adhesion gel: RR: 0.80, 95% CI: 0.58 to 1.10 (P=0.17);amnion graft:RR:0.63, 95% CI:0.44 to 0.91 (P=0.01). Conclusions: In conclusion, among various adjuvant therapies in secondary prevention of IUA, second look hysteroscopy and IUB can be considered as an option to reduce adhesion recurrence.

Impact of the severe familial hypercholesterolemia status on atherosclerotic risks

Risks of atherosclerotic events substantially vary even among patients with familial hypercholesterolemia (FH) with extremely high risk based on life-long exposure to high low-density lipoprotein cholesterol levels. This study aimed to examine the impact of the severe FH status defined by the International Atherosclerosis Society (IAS). Data of patients with FH (N = 1050, male = 490) who were admitted to Kanazawa University Hospital between 2000 and 2020 and who were followed up were retrospectively reviewed. The number of major adverse cardiac events (MACEs), including mortality associated with cardiovascular disease, acute coronary syndrome, and ischemic heart disease requiring coronary revascularization per 1000 person-years, was calculated. Hazard ratio was also calculated using Cox proportional model. Overall, 545 (51.9%) patients had severe FH. The median follow-up duration was 12.6 years. In total, 171 MACEs were recorded during the follow-up period. Severe FH was significantly associated with MACE (hazard ratio = 6.48, 95% confidence interval = 2.56–10.40, P = 1.2 × 10−5). The event rates per 1000 person-years in the primary prevention group of non-severe FH and severe FH, were 0.0 and 15.6, respectively. The event rates per 1000 person-years in the secondary prevention group of non-severe FH and severe FH, were 2.0 and 32.3, respectively. Patients with severe FH exhibited significantly higher risks in primary and secondary prevention settings. This simple criterion provides useful information for identifying patients with even higher risk who may need further management.

Myocardial scar characteristics by 3D-LGE cannot fully explain different arrhythmic event rates in primary and secondary prevention of sudden cardiac death

Abstract Background There is a noticeable difference in the incidence of ventricular arrhythmias among patients receiving defibrillator devices (ICD or CRT-D) for primary vs. secondary prevention of sudden cardiac death (SCD). The underlying reasons for this difference remain to be fully explained. Purpose To assess for differences in myocardial scar characteristics between patients who had defibrillator devices implanted in primary vs. secondary prevention scenarios, and their correlation with arrhythmic events. Methods In this single center retrospective study, patients who underwent late gadolinium enhancement (LGE) cardiac MRI for clinical purposes before the implantation of an ICD or CRT-D were included. Patients with channelopathies (n=2) or inappropriate imaging quality (n=7) were excluded. We used ADAS software to perform myocardial scar characterization in 3D-LGE datasets in all but 16 patients, in which 2D datasets were used. The primary endpoint was a composite of appropriate ICD therapy (appropriate shock or ATP), sustained ventricular tachycardia or SCD. Results A total of 116 patients (mean age 66±14 years, 81% male) were included, 40 (35%) with devices implanted in secondary prevention. During a median follow-up of 28 months (IQR 16-24), 23 events were identified (18 appropriate ICD therapy, 9 shocks and 9 ATP; 2 SCD; 3 sustained VT), 7 of which (30.4%) in the primary prevention group, and 16 (69.6%) in the secondary prevention group. The event rate was significantly higher in the secondary prevention setting (15.0 events per 100 persons-year [95% CI 7.7 – 22.4] vs. 4.1 events per 100 persons-year [95% CI 1.1 – 7.1]; p &amp;lt; 0.001). Despite a higher LVEF in the secondary prevention group (41 ± 14% vs. 30 ± 13%; p-value &amp;lt; 0.001), no statistically significant differences were found regarding scar tissue characteristics, namely scar and borderzone (BZ) mass, total channel mass, largest channel mass, number of channels and scar heterogeneity (BZ mass / scar mass ratio) – Table. Conclusion Despite the higher event rate in patients receiving defibrillator devices in secondary vs. prevention, no differences in myocardial scar characteristics were found between both groups. These findings suggest that arrhythmic risk is unlikely to be explained solely by the anatomical substrate, and support a greater role for the interplay between substrate and transient triggers.

Attainment of the low-density lipoprotein cholesterol treatment target and prognosis of heterozygous familial hypercholesterolemia

Abstract Background and aims No previous study has investigated the association between attainment of low-density lipoprotein (LDL) cholesterol treatment target and better prognosis in patients with familial hypercholesterolemia (FH). The current research aimed to examine the association between attainment of LDL cholesterol treatment target and major adverse cardiac events (MACEs) in patients with FH to validate the current LDL cholesterol treatment targets in primary (&amp;lt; 100 mg/dL) and secondary (&amp;lt; 70 mg/dL) prevention settings. Methods The data of patients with FH who were admitted to our university hospital between 2000 and 2020 and who were followed-up were retrospectively reviewed. The number of MACEs, including mortality associated with cardiovascular disease, unstable angina, and myocardial infarction per 1,000 person-years, was calculated for each stratum for the attainment of LDL cholesterol target. Results The median follow-up duration was 12.6 years. In total, 132 MACEs were recorded during the follow-up period. The numbers of patients who attained the LDL cholesterol target in the primary and secondary prevention groups were 228 (31.9%) and 40 (11.9%), respectively. The event rates per 1,000 person-years for LDL cholesterol levels of &amp;lt; 100 and ≥ 100 mg/dL in the primary prevention group were 2.6 and 4.4, respectively. The event rates per 1,000 person-years for LDL cholesterol levels of &amp;lt; 70 and ≥ 70mg/dL in the secondary prevention group were 15.3 and 27.5, respectively. Conclusion Attainment of the LDL cholesterol target is associated with better prognosis in patients with FH. However, the attainment rate is currently inadequate among Japanese.

Plasma levels of amyloid beta 1-40 are associated with ultrasonographic morphological characteristics related with carotid plaque vulnerability in individuals without cardiovascular disease

Abstract Background Amyloid-beta (1-40) (Αb40), a proinflammatory and pro-atherosclerotic peptide, is associated with concurrent subclinical atherosclerotic cardiovascular disease (ASCVD) and with major adverse cardiac events in both primary and secondary prevention settings conferring additive and reclassification value over traditional risk factors and risk scores. This evidence supports the hypothesis that Ab40 could be a biomarker of ASCVD. However, mechanistic data on the association of Αb40 with in vivo morphological characteristics of atherosclerosis related with plaque vulnerability are not available. Purpose To examine the association of Ab40 levels with characteristics of the carotid artery wall in the general population. Methods In the settings of the Athens Vascular registry, subjects without clinically overt ASCVD were consecutively recruited (n=301). Subclinical carotid atherosclerosis was assessed by ultrasonography and the images were subsequently analyzed using a dedicated software (AMS v3.03). The sum and maximal area of atherosclerotic plaques (PLQ) and the minimum echogenicity using grey scale median (GSM) of intima-media thickness (IMT, IMT_GSM) and atherosclerotic plaques (PLQ_GSM) were used as the main endpoints of the analysis. Αb40 was measured in plasma samples. Results Subjects with Ab40 levels in the highest tertile had higher prevalence of male sex, presence of carotid plaque atherosclerosis, higher sum and maximal PLQ are and lower GFR HDL-C levels and lower PLQ_GSM (p&amp;lt;0.05 for all). Ab40 in the highest vs. lower tertile was associated with higher sum and maximal plaque area (b-coefficient= 22.9 95% CI: 0.72, 45.1, p=0.43 and b-coefficient= 10.5 95% CI: 1.77, 19.3, p=0.019, for sum and maximal plaque area, respectively) after adjustment for traditional cardiovascular risk factors and GFR (core model). Moreover, Ab40 in the highest tertile was associated with decreased GSM of both IMT and PLQ in the carotid arteries (b-coefficient= -6.0 95% CI: -9.6, -2.36, p=0.001, for IMT and b-coefficient= -8.66 95% CI: -16.5, -0.79, p=0.31, for PLQ) after adjustment for the core model. Conclusion In individuals without clinically overt ASCVD, higher levels of Ab40 are associated with the larger atherosclerotic burden and with ultrasonographic characteristics related to higher plaque vulnerability. These findings suggest a mechanistic background for the established association of Ab40 with major adverse cardiovascular events.

Abstract 11402: Impact of the Severe Familial Hypercholesterolemia Status on Atherosclerotic Risks

Background and aims: Risk of atherosclerotic events substantially vary even among patients with familial hypercholesterolemia (FH) with extremely high risk based on life-long exposure to elevated LDL cholesterol. We aimed to examine impact of the severe FH status defined by the International Atherosclerosis Society (IAS). Methods: The data of patients with FH (N = 1,050, male = 490) who were admitted to Kanazawa University Hospital between 2000 and 2020 and who were followed-up were retrospectively reviewed. The number of MACEs, including mortality associated with cardiovascular disease, acute coronary syndrome, and ischemic heart disease requiring coronary revascularization per 1,000 person-years, was calculated. In addition, hazard ratio was calculated using Cox proportional model. Results: Overall, we identified 545 patients (51.9 %) with severe FH in this population. The median follow-up duration was 12.6 years. In total, 171 MACEs were recorded during the follow-up period. We found that severe FH was significantly associated with MACE (hazard ratio = 6.48, 95% confidence interval = 2.56 - 10.40, P = 1.2 х 10 -5 ). The event rates per 1,000 person-years for in the primary prevention group (non-severe FH and severe FH) were 0.0 and 15.6, respectively. The event rates per 1,000 person-years in the secondary prevention group (non-severe FH and severe FH) were 2.0 and 32.3, respectively. Conclusion: Patients with severe FH exhibited significant higher risks in primary as well as secondary prevention settings. This simple criterion provides us useful information to identify patients with even higher risk who may need further managements.

Global eligibility and cost effectiveness of icosapent ethyl in primary and secondary cardiovascular prevention.

Icosapent ethyl (IPE) is a purified eicosapentaenoic acid-only omega-3 fatty acid that significantly reduced cardiovascular (CV) events in patients receiving statins with established cardiovascular disease (CVD) and those with diabetes and additional risk factors in the pivotal REDUCE-IT trial. Since the publication of REDUCE-IT, there has been global interest in determining IPE eligibility in different patient populations, the proportion of patients who may benefit from IPE, and cost effectiveness of IPE in primary and secondary prevention settings. The aim of this review is to summarize information from eligibility and cost effectiveness studies of IPE to date. A total of sixteen studies were reviewed, involving 2,068,111 patients in the primary or secondary prevention settings worldwide. Up to forty-five percent of patients were eligible for IPE, depending on the selection criteria used (ie, REDUCE-IT criteria, US Food and Drug Administration label, Health Canada label, practice guidelines) and the population studied. Overall, eight cost-effectiveness studies across the United States, Canada, Germany, Israel, and Australia were included in this review and findings indicated that IPE is particularly cost effective in patients with established CVD.

Efficacy and Safety of Oral Factor XIa Inhibitors in Stroke Prevention: A Systematic Review and Meta-Analysis.

Despite preventive measures, stroke rates remain high in the primary and secondary prevention settings. Factor XIa inhibition may offer a novel, safe and effective antithrombotic option for stroke prevention. We conducted a systematic review and meta-analysis including all available randomized controlled clinical trials (RCTs) that investigated the efficacy and safety of factor XIa inhibitors versus controls in primary or secondary stroke prevention. The primary efficacy and safety outcomes of interest were symptomatic ischemic stroke (IS) and the composite of major bleeding and clinically relevant non-major bleeding. Four phase II dose-finding RCTs were included, comprising a total of 4732 patients treated with factor XIa inhibitors versus 1798 controls. Treatment with factor XIa inhibitors did not reduce the risk of IS compared to controls (RR: 0.89; 95% CI: 0.67-1.17). The composite of symptomatic IS and covert infarcts on brain MRI (RR: 1.01; 95% CI: 0.87-1.18), the composite of symptomatic IS and transient ischemic attack (TIA; RR: 0.78; 95% CI: 0.61-1.01), and the composite of major adverse cardiovascular events (RR: 1.07; 95% CI: 0.87-1.31) did not differ between the treatment groups. Treatment with factor XIa inhibitors did not increase the risk of the composite of major bleeding and clinically relevant non-major bleeding (RR: 1.19; 95% CI: 0.65-2.16), major bleeding alone (RR: 1.19; 95% CI: 0.64-2.22), intracranial bleeding (RR: 0.91; 95% CI: 0.26-3.19) or all-cause mortality (RR: 1.21; 95% CI: 0.77-1.90). This meta-analysis provides reassuring evidence regarding the safety of factor XIa inhibitors. These findings, coupled with potential signals of efficacy in reducing IS (and TIA), underscore the importance of ongoing phase III RCTs for providing definitive data regarding the effect of factor XIa inhibition on stroke prevention.