Consideration and Application of Lipoprotein(a) in the Risk Assessment of Atherosclerotic Cardiovascular Disease Risk in Adults.

Lipoprotein(a) (Lp[a]) is an low-density lipoprotein (LDL)-like particle in which apolipoprotein (apo) B is covalently bound to a plasminogen-like molecule called apo(a). A High level of Lp(a) has been demonstrated to be an independent, causal, and prevalent risk factor for atherosclerotic cardiovascular disease (ASCVD), as well as aortic valve disease, through mechanisms that promote atherogenesis, inflammation, and thrombosis. With reliable and accessible assays, Lp(a) level has been established to be associated linearly with the risk for ASCVD. The 2021 Canadian Cardiovascular Society Dyslipidemia Guidelines recommend measuring an Lp(a) level once in a person's lifetime as part of the initial lipid screening. The aim of this review is to provide an update and overview of the utility and application of Lp(a) level in the assessment and treatment of adults at risk for ASCVD, consistent with this guideline recommendation.

La lipoprotéine(a), ou Lp(a), est une lipoprotéine de basse densité dans laquelle l'apolipoprotéine B est liée de manière covalente à une molécule semblable au plasminogène, l'apolipoprotéine(a). On a démontré qu'un taux élevé de Lp(a) est un facteur de risque indépendant, causal et fréquent d'athérosclérose cardiovasculaire (ASCV) et de valvulopathie aortique, en raison de mécanismes qui favorisent l'athérogénèse, l'inflammation et la thrombose. Des épreuves fiables et accessibles ont permis d'établir que le taux de Lp(a) était associé de façon linéaire à un risque d'ASCV. Dans ses lignes directrices de 2021 sur la prise en charge de la dyslipidémie, la Société cardiovasculaire du Canada recommande de mesurer le taux de Lp(a) une fois au cours de la vie d'une personne, dans le cadre du dépistage initial des lipides. Le présent article vise à fournir une mise à jour et un compte rendu de l'utilité et de l'application du taux de Lp(a) dans l'évaluation et le traitement des adultes présentant un risque d'ASCV, conformément à cette recommandation issue des lignes directrices.

Factors Associated With Coronary Angiography Performed Within 6 Months of Randomization to the Conservative Strategy in the ISCHEMIA Trial.

BACKGROUND: ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) did not find an overall reduction in cardiovascular events with an initial invasive versus conservative management strategy in chronic coronary disease; however, there were conservative strategy participants who underwent invasive coronary angiography early postrandomization (within 6 months). Identifying factors associated with angiography in conservative strategy participants will inform clinical decision-making in patients with chronic coronary disease. METHODS: Factors independently associated with angiography performed within 6 months of randomization were identified using Fine and Gray proportional subdistribution hazard models, including demographics, region of randomization, medical history, risk factor control, symptoms, ischemia severity, coronary anatomy based on protocol-mandated coronary computed tomography angiography, and medication use. RESULTS: Among 2591 conservative strategy participants, angiography within 6 months of randomization occurred in 8.7% (4.7% for a suspected primary end point event, 1.6% for persistent symptoms, and 2.6% due to protocol nonadherence) and was associated with the following baseline characteristics: enrollment in Europe versus Asia (hazard ratio [HR], 1.81 [95% CI, 1.14-2.86]), daily and weekly versus no angina (HR, 5.97 [95% CI, 2.78-12.86] and 2.63 [95% CI, 1.51-4.58], respectively), poor to fair versus good to excellent health status (HR, 2.02 [95% CI, 1.23-3.32]) assessed with Seattle Angina Questionnaire, and new/more frequent angina prerandomization (HR, 1.80 [95% CI, 1.34-2.40]). Baseline low-density lipoprotein cholesterol <70 mg/dL was associated with a lower risk of angiography (HR, 0.65 [95% CI, 0.46-0.91) but not baseline ischemia severity nor the presence of multivessel or proximal left anterior descending artery stenosis >70% on coronary computed tomography angiography. CONCLUSIONS: Among ISCHEMIA participants randomized to the conservative strategy, angiography within 6 months of randomization was performed in <10% of patients. It was associated with frequent or increasing baseline angina and poor quality of life but not with objective markers of disease severity. Well-controlled baseline low-density lipoprotein cholesterol was associated with a reduced likelihood of angiography. These findings point to the importance of a comprehensive assessment of symptoms and a review of guideline-directed medical therapy goals when deciding the initial treatment strategy for chronic coronary disease. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01471522.

Factors associated with coronary angiography performed within 6 months of randomization to the conservative strategy in the ISCHEMIA Trial

BACKGROUND: ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) did not find an overall reduction in cardiovascular events with an initial invasive versus conservative management strategy in chronic coronary disease; however, there were conservative strategy participants who underwent invasive coronary angiography early postrandomization (within 6 months). Identifying factors associated with angiography in conservative strategy participants will inform clinical decision-making in patients with chronic coronary disease. METHODS: Factors independently associated with angiography performed within 6 months of randomization were identified using Fine and Gray proportional subdistribution hazard models, including demographics, region of randomization, medical history, risk factor control, symptoms, ischemia severity, coronary anatomy based on protocol-mandated coronary computed tomography angiography, and medication use. RESULTS: Among 2591 conservative strategy participants, angiography within 6 months of randomization occurred in 8.7% (4.7% for a suspected primary end point event, 1.6% for persistent symptoms, and 2.6% due to protocol nonadherence) and was associated with the following baseline characteristics: enrollment in Europe versus Asia (hazard ratio [HR], 1.81 [95% CI, 1.14­2.86]), daily and weekly versus no angina (HR, 5.97 [95% CI, 2.78­12.86] and 2.63 [95% CI, 1.51­4.58], respectively), poor to fair versus good to excellent health status (HR, 2.02 [95% CI, 1.23­3.32]) assessed with Seattle Angina Questionnaire, and new/more frequent angina prerandomization (HR, 1.80 [95% CI, 1.34­2.40]). Baseline low-density lipoprotein cholesterol <70 mg/dL was associated with a lower risk of angiography (HR, 0.65 [95% CI, 0.46­0.91) but not baseline ischemia severity nor the presence of multivessel or proximal left anterior descending artery stenosis >70% on coronary computed tomography angiography. CONCLUSIONS: Among ISCHEMIA participants randomized to the conservative strategy, angiography within 6 months of randomization was performed in <10% of patients. It was associated with frequent or increasing baseline angina and poor quality of life but not with objective markers of disease severity. Well-controlled baseline low-density lipoprotein cholesterol was associated with a reduced likelihood of angiography. These findings point to the importance of a comprehensive assessment of symptoms and a review of guideline-directed medical therapy goals when deciding the initial treatment strategy for chronic coronary disease.

Effects of adaptive or fixed thresholds and different platforms on the assessment of plaque characteristics using coronary computed tomography angiography.

BACKGROUND: Coronary computed tomography angiography (CCTA) is used to evaluate components of atherosclerosis. Either adaptive or diverse, fixed Hounsfield Units (HU) are used to define components such as low attenuation (LAP), mixed (MP) and calcified plaque (CP). Comparisons of different platforms and different thresholding approaches have not been extensively evaluated. We compare two fixed threshold options to an adaptive threshold option within a specific platform and to fixed threshold options measured with another platform. METHODS: Coronary segments (n â€‹= â€‹24) of good image quality, with well-defined boundaries and representing a broad range of atheroma were analyzed for LAP, MP and CP. Thresholds for LAP vs MP and MP vs CP were either Fixed30/350, Fixed75/350 or based on an automatically determined Adaptive option. Pearson correlation and Bland-Altman analyses were undertaken. RESULTS: Within a single platform, measures were highly correlated irrespective of use of Adaptive or Fixed30/350 and Fixed75/350 thresholds (R â€‹≥ â€‹0.819, p â€‹< â€‹0.000001). The correlation slope for measures of LAP progressively diminished comparing the Adaptive versus Fixed30/350 and the Fixed75/350 versus the Fixed30/350 approaches but bias was small. Between-platform comparisons yielded less optimal results, particularly with respect to measures of LAP and with one platform yielding both very small LAP volumes and very small ranges of volumes. CONCLUSION: Measures of plaque components are highly correlated irrespective of use of Adaptive or Fixed threshold approaches within a given platform. But measures are more affected by the specific proprietary algorithms employed than by specific thresholding options, especially for LAP.

The effectiveness of sodium-glucose co-transporter 2 inhibitors on cardiorenal outcomes: an updated systematic review and meta-analysis.

BACKGROUND: The 2022 Canadian Cardiovascular Society (CCS) cardiorenal guideline provided clinical recommendations on sodium-glucose co-transport 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) use. Since then, additional trials of relevance for SGLT2i have been published. This update re-evaluates the clinical recommendations for using SGLTi and their indirect comparison with existing evidence on GLP-1RA as compared to the standard of care to reduce cardiorenal morbidity and mortality. METHODS: We updated our existing search and screening of the literature from September 2021 to April 2023 for randomized controlled trials of SGLT2i and GLP-1RA with placebo control. We conducted risk of bias assessment, data extraction and updated our meta-analysis of studies with similar interventions and components. The certainty of the evidence was determined using GRADE. RESULTS: Evidence from three new trials and additional results from an updated existing trial on SGLT2i met our inclusion criteria after an updated search. Across all the included studies, the total sample size was 151,023 adults, with 90,943 in SGLT2i trials and 60,080 in GLP-1 RA trials. The mean age ranged from 59.9 to 68.4 years. Compared with standard care, the use of SGLT2i and GLP-1 RA showed significant reductions in the outcomes of cardiovascular (CV) mortality (14% & 13%), any-cause mortality (12% & 12%), major adverse CV events (MACE) (11% & 14%), heart failure (HF) hospitalization (30% & 9%), CV death or HF hospitalization (23% & 11%), and kidney composite outcome (32% & 22%). In participants with T2D, both classes demonstrated significant cardiorenal protection. But, only GLP-1RA showed a reduction in non-fatal stroke (16%) and only SGLT2i showed a reduction in HF hospitalization (30%) in this population of people living with T2D. CONCLUSIONS: This updated and comprehensive meta-analysis substantiates and strengthens the clinical recommendations of the CCS cardiorenal guidelines.

Angiographic characteristics of patients with STEMI and COVID-19: Insights from NACMI registry.

BACKGROUND: To date, there has been no independent core lab angiographic analysis of patients with COVID-19 and STEMI. The study characterized the angiographic parameters of patients with COVID-19 and STEMI. METHODS: Angiograms of patients with COVID-19 and STEMI from the North American COVID-19 Myocardial Infarction (NACMI) Registry were sent to a Core Laboratory in Vancouver, Canada. Culprit lesion(s), Thrombolysis In Myocardial Infarction (TIMI) flow, Thrombus Grade Burden (TGB), and percutaneous coronary intervention (PCI) outcome were assessed. RESULTS: From 234 patients, 74% had one culprit lesion, 14% had multiple culprits and 12% had no culprit identified. Multivessel thrombotic disease and multivessel CAD were found in 27% and 53% of patients, respectively. Stent thrombosis accounted for 12% of the presentations and occurred in 55% of patients with previous coronary stents. Of the 182 who underwent PCI, 60 (33%) had unsuccessful PCI due to post-PCI TIMI flow <3 (43/60), residual high thrombus burden (41/60) and/or thrombus related complications (27/60). In-hospital mortality for successful, partially successful, and unsuccessful PCI was 14%, 13%, and 27%, respectively. Unsuccessful PCI was associated with increased risk of in-hospital mortality (risk ratio [RR] 1.96; 95% CI: 1.05-3.66, P = .03); in the adjusted model this estimate was attenuated (RR: 1.24; 95% CI: 0.65-2.34, P = .51). CONCLUSION: In patients with COVID-19 and STEMI, thrombus burden was pervasive with notable rates of multivessel thrombotic disease and stent thrombosis. Post-PCI, persistent thrombus and sub-optimal TIMI 3 flow rates led to one-third of the PCI's being unsuccessful, which decreased over time but remained an important predictor of in-hospital mortality.

Efficacy and safety of bempedoic acid in patients with heterozygous familial hypercholesterolemia: analysis of pooled patient-level data from phase 3 clinical trials.

BACKGROUND: Patients with heterozygous familial hypercholesterolemia (HeFH) often cannot reach guideline-recommended low-density lipoprotein cholesterol (LDL-C) goals despite multidrug therapy. OBJECTIVE: To evaluate the efficacy and safety of bempedoic acid as an add-on therapy for lowering LDL-C in patients with HeFH. METHODS: Pooled data from two 52-week phase 3 clinical trials of patients with atherosclerotic cardiovascular disease and/or HeFH receiving maximally tolerated statin therapy (randomized 2:1 to bempedoic acid or placebo) were analyzed by HeFH status. Endpoints included changes from baseline to week 12 (and up to week 52) in LDL-C and other lipid parameters, achievement of LDL-C goals, and safety. RESULTS: A total of 217 (bempedoic acid, 146; placebo, 71) patients with HeFH and 2,792 (bempedoic acid, 1,864; placebo, 928) without HeFH were included (mean baseline LDL-C, 172.8 mg/dL and 102.6 mg/dL, respectively). Bempedoic acid significantly lowered LDL-C at week 12 vs. placebo regardless of HeFH status (with HeFH, -21.2%; without HeFH, -18.2% [both P<0.0001]). Bempedoic acid significantly reduced other lipid parameters and high-sensitivity C-reactive protein vs. placebo regardless of HeFH status (all P≤0.01). Among patients with HeFH treated with bempedoic acid, 32% and 27% achieved LDL-C <100 mg/dL at weeks 12 and 52, respectively. Overall treatment-emergent adverse event incidence was comparable across all four groups (74.7-77.5%). CONCLUSION: Bempedoic acid significantly lowered LDL-C levels vs. placebo and was generally well tolerated in all patients, with no new safety findings in patients with HeFH, despite more intensive lipid-lowering therapy in patients with vs. without HeFH.

Primary and Secondary Cardiovascular and Kidney Prevention With Canagliflozin: Insights From the CANVAS Program and CREDENCE Trial.

BACKGROUND: This study evaluated the effects of canagliflozin in patients with type 2 diabetes with and without prevalent cardiovascular disease (secondary and primary prevention). METHODS AND RESULTS: This was a pooled participant-level analysis of the CANVAS (Canagliflozin Cardiovascular Assessment Study) Program and CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial. The CANVAS Program included participants with type 2 diabetes at elevated cardiovascular risk, whereas the CREDENCE trial included participants with type 2 diabetes and albuminuric chronic kidney disease. Hazard ratios (HRs) with interaction terms were obtained from Cox regression models to estimate relative risk reduction with canagliflozin versus placebo across the primary and secondary prevention groups. We analyzed 5616 (38.9%) and 8804 (61.1%) individuals in the primary and secondary prevention subgroups, respectively. Primary versus secondary prevention participants were on average younger (62.2 versus 63.8 years of age) and more often women (42% versus 31%). Canagliflozin reduced the risk of major adverse cardiovascular events (HR, 0.84 [95% CI, 0.76-0.94]) consistently across primary and secondary prevention subgroups (Pinteraction=0.86). Similarly, no treatment effect heterogeneity was observed with canagliflozin for hospitalization for heart failure, cardiovascular death, end-stage kidney disease, or all-cause mortality (all Pinteraction>0.5). CONCLUSIONS: Canagliflozin reduced cardiovascular and kidney outcomes with no statistical evidence of heterogeneity for the treatment effect across the primary and secondary prevention subgroups in the CANVAS Program and CREDENCE trial. Although studies on the optimal implementation of canagliflozin within these populations are warranted, these results reinforce canagliflozin's role in cardiorenal prevention and treatment in individuals with type 2 diabetes. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01032629, NCT01989754, NCT02065791.

Sex differences in the presentation, treatment and outcomes of patients with homozygous familial hypercholesterolemia.

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare, autosomal semi-dominant lipid metabolism disorder characterized by extremely high low-density lipoprotein cholesterol (LDL-C) levels and premature cardiovascular disease. The objective of this study was to investigate sex-differences in the treatment and outcomes of patients with HoFH. METHODS: We examined clinical characteristics, lipid-lowering therapy (LLT), and cardiovascular events using descriptive statistics of patients in the Canadian HoFH registry. Major adverse cardiovascular events (MACE) were defined as the composite of cardiovascular death, non-fatal myocardial infarction, and stroke. Sex differences between continuous and categorical variables were analyzed using Mann-Whitney U test and Fisher's Exact test, respectively. RESULTS: This study included 48 patients (27 (56%) female). The median age at diagnosis in females was 14.0 (interquartile range (IQR) 9.0-30.0) and in males was 8.0 (IQR 2.0-23.0) (p = 0.07). Baseline clinical characteristics were comparable between both sexes. The median baseline LDL-C was 12.7 mmol/L (10.0-18.3) in females and 15.3 (10.5-20.0) in males (p = 0.51). Follow up LDL-C levels were 7.6 mmol/L (IQR 4.8-11.0) in females and 6.3 (IQR 4.6-7.5) in males (p = 0.1). Most patients were taking 3 or more LLTs, with comparable proportions in both sexes (p = 0.26). Apheresis was similar in both sexes, 14 (51.8%) vs. 10 (47.6%) (p = 0.2). Over a mean of 10 years of follow-up, MACE occurred in 3 females (11.1%) and 4 males (19.1%) (p = 0.2). CONCLUSION: Lipid levels and treatment were similar between sexes. MACE occurred in similar proportions between sexes, indicating that HoFH offsets the inherently lower cardiovascular risk in pre-menopausal females. Further investigation into sex-differences in HoFH in larger sample sizes is warranted.

Recommendations for statin management in primary prevention: disparities among international risk scores.

BACKGROUND AND AIMS: Statin recommendations in primary prevention depend upon risk algorithms. Moreover, with intermediate risk, risk enhancers and de-enhancers are advocated to aid decisions. The aim of this study was to compare algorithms used in North America and Europe for the identification of patients warranting statin or consideration of risk enhancers and de-enhancers. METHODS: A simulated population (n = 7680) equal in males and females, with/without smoking, aged 45-70 years, total cholesterol 3.5-7.0 mmol/L, high-density lipoprotein cholesterol 0.6-2.2 mmol/L, and systolic blood pressure 100-170 mmHg, was evaluated. High, intermediate, and low risks were determined using the Framingham Risk Score (FRS), Pooled Cohort Equation (PCE), four versions of Systematic Coronary Risk Evaluation 2 (SCORE2), and Multi-Ethnic Study of Atherosclerosis (MESA) algorithm (0-1000 Agatston Units). RESULTS: Concordance for the three levels of risk varied from 19% to 85%. Both sexes might be considered to have low, intermediate, or high risk depending on the algorithm applied, even with the same burden of risk factors. Only SCORE2 (High Risk and Very High Risk versions) identified equal proportions of males and females with high risk. Excluding MESA, the proportion with moderate risk was 25% (SCORE2, Very High Risk Region), 32% (FRS), 39% (PCE), and 45% (SCORE2, Low Risk Region). CONCLUSION: Risk algorithms differ substantially in their estimation of risk, recommendations for statin treatment, and use of ancillary testing, even in identical patients. These results highlight the limitations of currently used risk-based approaches for addressing lipid-specific risk in primary prevention.

Real-World Insights into Evolocumab Use in Patients with Hyperlipidemia Across Five Countries: Analysis from the ZERBINI Study.

INTRODUCTION: This study characterizes patients receiving evolocumab in clinical practice and assesses treatment effectiveness, safety and persistence outcomes across five countries. METHODS: This retrospective and prospective observational study enrolled patients initiated on evolocumab during August 2017 to July 2019 at 49 sites across Canada, Mexico, Colombia, Saudi Arabia and Kuwait. Medical records data were extracted within 6 months prior to (baseline) and every 3 months for 12 months post evolocumab initiation and reported as available. RESULTS: A total of 578 patients were enrolled (40.1% female, median age 60 [interquartile range (IQR) 51-68] years); 83.7% had atherosclerotic cardiovascular disease and/or familial hypercholesterolemia. Median low-density lipoprotein cholesterol (LDL-C) at baseline was 3.4 (IQR 2.7-4.2) mmol/L (131.5 [IQR 104.4-162.4] mg/dL), with 75.6% of patients receiving a statin (59.2% high intensity). Compared to baseline, the median lowest LDL-C was reduced by 70.2% and remained stable over 12 months of treatment. Guideline-recommended LDL-C thresholds < 1.8, < 1.4 and < 1.0 mmol/L (< 70, < 55 and < 40 mg/dL) were achieved by 75.3%, 63.6% and 47.4% of patients. LDL-C outcomes were consistent across high- and very high-risk patients. Background lipid-lowering therapy remained relatively stable. No serious treatment-emergent adverse events were reported, and persistence to evolocumab was 90.2% at 12 months. CONCLUSION: These findings provide real-world evidence that evolocumab use is in accordance with its international guideline-recommended place in dyslipidemia therapy, as well as confirmation of its effectiveness and safety in a heterogeneous population. Evolocumab can address a healthcare gap in the management of dyslipidemia by increasing the proportion of patients achieving LDL-C goals recommended to lower cardiovascular risk.

Epidemiology and treatment of heart failure with chronic obstructive pulmonary disease in Canadian primary care.

AIMS: Heart failure (HF) and chronic obstructive pulmonary disease (COPD) are largely managed in primary care, but their intersection in terms of disease burden, healthcare utilization, and treatment is ill-defined. METHODS AND RESULTS: We examined a retrospective cohort including all patients with HF or COPD in the Canadian Primary Care Sentinel Surveillance Network from 2010 to 2018. The population size in 2018 with HF, COPD, and HF with COPD was 15 778, 27 927, and 4768 patients, respectively. While disease incidence declined, age-sex-standardized prevalence per 100 population increased for HF alone from 2.33 to 3.63, COPD alone from 3.44 to 5.96, and COPD with HF from 12.70 to 15.67. Annual visit rates were high and stable around 8 for COPD alone but declined significantly over time for HF alone (9.3-8.1, P = 0.04) or for patients with both conditions (14.3-11.9, P = 0.006). For HF alone, cardiovascular visits were common (29.4%), while respiratory visits were infrequent (3.5%), with the majority of visits being non-cardiorespiratory. For COPD alone, respiratory and cardiovascular visits were common (16.4% and 11.3%) and the majority were again non-cardiorespiratory. For concurrent disease, 39.0% of visits were cardiorespiratory. The commonest non-cardiorespiratory visit reasons were non-specific symptoms or signs, endocrine, musculoskeletal, and mental health. In patients with HF with and without COPD, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor use was similar, while mineralocorticoid receptor antagonist use was marginally higher with concurrent COPD. Beta-blocker use was initially lower with concurrent COPD compared with HF alone (69.3% vs. 74.0%), but this progressively declined by 2018 (74.5% vs. 73.5%). CONCLUSIONS: The prevalence of HF and COPD continues to rise. Although patients with either or both conditions are high utilizers of primary care, the majority of visits relate to non-cardiorespiratory comorbidities. Medical therapy for HF was similar and the initially lower beta-blocker utilization disappeared over time.

Atherosclerotic Coronary Plaque Regression and Risk of Adverse Cardiovascular Events: A Systematic Review and Updated Meta-Regression Analysis.

Importance: The association between changes in atherosclerotic plaque induced by lipid-lowering therapies (LLTs) and reduction in major adverse cardiovascular events (MACEs) remains controversial. Objective: To evaluate the association between coronary plaque regression assessed by intravascular ultrasound (IVUS) and MACEs. Data Sources: A comprehensive, systematic search of publications in PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science was performed. Study Selection: Clinical prospective studies of LLTs reporting change in percent atheroma volume (PAV) assessed by IVUS and describing MACE components were selected. Data Extraction and Synthesis: Reporting was performed in compliance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The association between mean change in PAV and MACEs was analyzed by meta-regression using mixed-effects, 2-level binomial logistic regression models, unadjusted and adjusted for clinical covariates, including mean age, baseline PAV, baseline low-density lipoprotein cholesterol level, and study duration. Main Outcome and Measures: Mean PAV change and MACE in intervention and comparator arms were assessed in an updated systematic review and meta-regression analysis of IVUS trials of LLTs that also reported MACEs. Results: This meta-analysis included 23 studies published between July 2001 and July 2022, including 7407 patients and trial durations ranging from 11 to 104 weeks. Mean (SD) patient age ranged from 55.8 (9.8) to 70.2 (7.6) years, and the number of male patients from 245 of 507 (48.3%) to 24 of 26 (92.3%). Change in PAV across 46 study arms ranged from -5.6% to 3.1%. The number of MACEs ranged from 0 to 72 per study arm (17 groups [37%] reported no events, 9 [20%] reported 1-2 events, and 20 [43%] reported ≥3 events). In unadjusted analysis, a 1% decrease in mean PAV was associated with 17% reduced odds of MACEs (unadjusted OR, 0.83; 95% CI, 0.71-0.98; P = .03), and with a 14% reduction in MACEs in adjusted analysis (adjusted OR, 0.86; 95% CI, 0.75-1.00; P = .050). Further adjustment for cardiovascular risk factors showed a 19% reduced risk (adjusted OR, 0.81; 95% CI, 0.68-0.96; P = .01) per 1% decrease in PAV. A 1% reduction of PAV change between intervention and comparator arms within studies was also associated with a significant 25% reduction in MACEs (OR, 0.75; 95% CI, 0.56-1.00; P = .046). Conclusions and Relevance: In this meta-analysis, regression of atherosclerotic plaque by 1% was associated with a 25% reduction in the odds of MACEs. These findings suggest that change in PAV could be a surrogate marker for MACEs, but given the heterogeneity in the outcomes, additional data are needed.

Evaluation of the efficacy and safety of bempedoic acid in women and men: Pooled analyses from phase 3 trials.

BACKGROUND AND AIMS: Sex-specific differences in the response to lipid-lowering therapies have been reported. Here, we assessed the effect of bempedoic acid in women and men using pooled, patient-level data from four phase 3 clinical trials of bempedoic acid. METHODS: Patients were grouped into two pools: 1) atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (HeFH) "on statins" and 2) "low-dose or no statin". Percent changes from baseline to at least week 12 in low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), apolipoprotein B (Apo B), and high-sensitivity C-reactive protein (hsCRP), as well as safety, were analyzed by statin pool and sex. RESULTS: Overall, 3623 patients were included (bempedoic acid, 2425; placebo, 1198). Significant reductions in lipid parameters and hsCRP were observed with bempedoic acid vs. placebo in both sexes in the ASCVD and/or HeFH on statins (n = 3009) and the low-dose or no statin (n = 614) pools (p ≤ 0.002). Compared with men, women had significantly greater placebo-corrected reductions in LDL-C (-21.2% vs. -17.4%; p = 0.044), non-HDL-C (-17.3% vs. -12.1%; p = 0.003), TC (-13.8% vs. -10.5%; p = 0.012), and Apo B (-16.0% vs. -11.3%; p = 0.004) in the ASCVD and/or HeFH on statins pool. Women had similar reductions to men in lipid parameters in the low-dose or no statin pool and hsCRP in both pools. The safety of bempedoic acid was comparable between sexes. CONCLUSIONS: In this pooled analysis, women experienced significant improvements in levels of LDL-C and other lipid parameters with bempedoic acid.

Statin associated muscle symptoms (SAMS): strategies for prevention, assessment and management.

INTRODUCTION: Statins are the cornerstone for atherosclerotic cardiovascular disease risk reduction with recognized efficacy in primary and secondary prevention. Despite this, they remain underutilized due to concerns regarding adverse effects. Statin-associated muscle symptoms (SAMS) are the most frequent cause of medication intolerance and discontinuation with a prevalence estimated at 10%, regardless of causality, with the consequence of increased risk of adverse cardiovascular outcomes. AREAS COVERED: This clinical perspective reviews recent developments in mechanisms underlying the pathogenesis of statin myopathy, the role of the nocebo effect in perception of statin intolerance, and explores diverse components endorsed by international societies in establishing a statin intolerance syndrome. Non-statin drug alternatives that reduce low-density lipoprotein-cholesterol are also discussed, with emphasis on therapies with established effects on cardiovascular outcomes. EXPERT OPINION: Ultimately, a patient-centered clinical approach to managing SAMS is proposed to optimize statin tolerability, achieve guideline-recommended therapeutic goals and improve cardiovascular outcomes.

Bempedoic acid lowers high-sensitivity C-reactive protein and low-density lipoprotein cholesterol: Analysis of pooled data from four phase 3 clinical trials.

BACKGROUND AND AIMS: High-sensitivity C-reactive protein (hsCRP), a marker for atherosclerotic cardiovascular disease risk, is reduced by bempedoic acid. We assessed the relationship between changes in low-density lipoprotein cholesterol (LDL-C) and hsCRP in relation to baseline statin use. METHODS: Pooled data from four phase 3 trials (patients on maximally tolerated statins [Pool 1] and patients receiving no or low-dose statins [Pool 2]) were used to determine the proportion of patients with baseline hsCRP ≥2 mg/L who achieved hsCRP <2 mg/L at week 12. The percentage of patients who achieved hsCRP <2 mg/L and guideline-recommended LDL-C (Pool 1, <70 mg/dL; Pool 2, <100 mg/dL) was determined for patients on statins in Pool 1 and those not on statins in Pool 2, as was the correlation between percent changes in hsCRP and LDL-C. RESULTS: Overall, 38.7% in Pool 1 and 40.7% in Pool 2 with baseline hsCRP ≥2 mg/L achieved hsCRP <2 mg/L with bempedoic acid, with little effect from background statin. Among patients taking a statin in Pool 1 or not taking a statin in Pool 2, 68.6% and 62.4% achieved hsCRP <2 mg/L. Both hsCRP <2 mg/L and United States guideline-recommended LDL-C were achieved more often with bempedoic acid vs. placebo (20.8% vs. 4.3%, respectively, in Pool 1 and 32.0% vs. 5.3%, in Pool 2). Changes in hsCRP and LDL-C were only weakly correlated (Pool 1, r = 0.112; Pool 2, r = 0.173). CONCLUSIONS: Bempedoic acid significantly reduced hsCRP irrespective of background statin therapy; the effect was largely independent of LDL-C lowering.