Adverse Cardiovascular Research Articles

Machine learning approach for detection of MACE events within clinical trial data.

Randomized controlled trials (RCTs) are the gold standard for clinical research but may not accurately reflect the impact of medicines in real-world settings. Supplementing RCTs with insights from real-world data (RWD) can address known limitations by including more diverse patient populations, additional types of sites-of-care, and practices more representative of the care most people receive. One current challenge in using RWD is the lack of an algorithmic approach to identifying outcomes. To address this, machine learning models for identifying a frequently used outcome, Major Adverse Cardiovascular Events (MACE), were developed in Clinical Trial Data (CTD). Anonymized CTD sourced from the Medidata Enterprise Data Store were used to develop model features on the condition that they would be useful for labelling MACE events and that they could also be found in RWD. These features were used to train three random forest models to identify each component of 3-point MACE in a patient's clinical trial journey. Performance metrics for the models are presented (recall = 0.72 [0.07], precision = 0.68 [0.12] - mean, [SD]) along with the top contributing features. We show that the models can be tuned specifically to replicate the adjudication panels' results and present a cost-benefit analysis for deploying such models in clinical trial settings. We demonstrate the viability of using advanced algorithms for identifying clinical outcomes in prospective clinical trials. Deployment of such models could reduce the resources required to conduct RCTs. Extending such models to RWD would facilitate approval of pragmatic clinical trials for regulatory submissions.

Modified Balloon Use After Rotational Atherectomy Reduces Major Adverse Cardiovascular Event Rates in Severely Calcified Coronary Lesions: A Systematic Review and Meta-Analysis

Modified Balloon Use After Rotational Atherectomy Reduces Major Adverse Cardiovascular Event Rates in Severely Calcified Coronary Lesions: A Systematic Review and Meta-Analysis

Non-steroidal Immune Modulating Therapies and Reduced Risk of Adverse Cardiovascular Events in Dermatomyositis and Polymyositis: A Cohort Study in the All of Us Research Program.

Non-steroidal Immune Modulating Therapies and Reduced Risk of Adverse Cardiovascular Events in Dermatomyositis and Polymyositis: A Cohort Study in the All of Us Research Program.

Biologics and Oral Small Molecules Are Not Associated With Increased Major Adverse Cardiovascular Events or Venous Thromboembolism in Inflammatory Bowel Disease.

Biologics and oral small molecules (OSM) effectively treat inflammatory bowel disease (IBD), but some are linked to higher risks of major adverse cardiovascular events (MACE) and venous thromboembolism (VTE). This study evaluates the MACE and VTE risks in IBD patients treated with biologics or OSM. Using the TrinNetX multi-institutional database, we examined MACE and VTE in adult IBD patients on biologics and compared them to IBD patients not on biologics. We also compared IBD patients on OSM to those not on OSM. We performed 1:1 propensity score matching. MACE (myocardial infarction [MI], stroke, and all-cause mortality) and VTE were assessed from 30 days to 3 years after drug prescription. After matching, IBD patients on biologics had reduced risk of MI, stroke, and all-cause mortality at 1 year, compared to those not on biologics (P < .05). No significant difference in VTE was observed (P = .5). At 3 years, biologic-treated patients had lower risks of MI, stroke, all-cause mortality, and VTE (P < .05). Inflammatory bowel disease patients on OSM showed no significant differences in MI, stroke, or VTE at 1 and 3 years, but had lower all-cause mortality (P < .05). In older IBD patients with at least 1 cardiovascular risk factor, OSM usage showed no significant difference in MI, stroke, or VTE risk compared to nonusers; however, all-cause mortality was decreased at 3 years (P < .05). Inflammatory bowel disease patients treated with biologics or OSM were not at increased risk of MACE or VTE. Although further studies and longer follow-up periods are needed to confirm these findings, our results provide reassurance regarding the safety of these medications in IBD.

Abstract 4136930: Plasminogen Activator Urokinase Receptor (PLAUR) Levels are a Predictor of Adverse Cardiovascular Outcomes in the General Population, Independent of High-Sensitive CRP (hs-CRP)

Background: The gene Plasminogen Activator Urokinase Receptor (PLAUR) encodes the urokinase plasminogen activator surface receptor (uPAR), which upon cleavage releases Soluble Urokinase Plasminogen Activator Receptor (suPAR). SuPAR has emerged as a novel biomarker of inflammation and immunity and is associated with adverse cardiovascular events, particularly coronary artery disease (CAD), regardless of hs-CRP levels, a well-established inflammatory biomarker. However, whether the PLAUR gene predicts adverse cardiovascular events remains uncertain. Methods: We investigated the relationship between PLAUR levels, measured via Olink Immunoassay, in 40,790 individuals from the UK Biobank, and the occurrence of adverse cardiovascular events such as myocardial infarction (MI), as well as all-cause and cardiovascular mortality. Our analysis involved the use of Cox and Fine and Gray proportional hazards models, adjusting for age, sex, race, HDL, LDL, triglyceride levels, BMI, prevalence of hypertension (HTN), prevalence of type 2 diabetes (T2D), smoking history, and use of blood pressure and cholesterol medications. Main Outcomes: The primary outcome was a composite outcome of cardiovascular mortality and MI and the secondary outcome was all-cause mortality. Results: The mean (SD) age was 58 (8) years, 45% men and 94% white. During a median follow-up of 14 (interquartile range 12.3 – 15) years, 7.9% of the population had an MI, 2.7% suffered cardiovascular death, 9.5% all-cause mortality. After adjusting for aforementioned demographic and clinical factors, as well as medication usage, each standard deviation increase in PLAUR levels was associated with a heightened risk of incident non-fatal MI and cardiovascular (CV) death, with a hazard ratio (HR) of 2.31 (95% CI 2.00-2.45), and all-cause mortality, with an HR of 3.81 (95% CI 3.48-4.18). Even after further adjustment for hs-CRP levels, PLAUR levels remained predictive of non-fatal MI and CV death (HR 2.03, 95% CI 1.83-2.26) and all-cause mortality (HR 3.43, 95% CI 3.12-3.77). Furthermore, in a fully adjusted Cox regression model, a significant interaction between PLAUR levels and sex (p = 0.0003) was observed in predicting the primary outcome. The interaction was found to have a stronger predictive value in females compared to males. Conclusion: PLAUR levels are a strong predictor of adverse cardiovascular outcomes in the general population, independent of traditional risk factors and inflammation.

Abstract 4137695: Bundle Branch Block(BBB) is Independently Associated With Adverse Cardiovascular Outcomes in Patients With Heart Failure With Preserved Ejectionfraction(HFPEF): A Propensity Score Matched Analysis

Background: Ventricular dyssynchrony due to BBB can cause adverse cardiovascular(CV) outcomes in HF with reduced EF and is known to occur in HFpEF but its independent impact on is unclear. Objective: To determine if BBB is an independent risk factor for adverse HF outcomes in HFpEF and the impact of atrial fibrillation (AF).. Methods: We studied the impact of BBB in HFpEF utilizing propensity score(PS) matched cohorts without and with BBB from the TOPCAT Americas trial to account for confounding by other co-morbidities. Outcomes analyzed included the TOPCAT primary outcome, CV death&amp;hospitalization (CVH), sudden death, pump failure death (PFD), HF hospitalizations(H), and progression of HF. The impact of concomitant AF ( defined as any AF or AF on ECG) on these outcomes with and without BBB was analyzed. Results: 329 pts with HFpEF&amp;BBB were PS matched for 24 demographic&amp;disease state variables, BNP strata and AF status with a cohort of 329 pts with HFpEF without BBB. BBB was associated with increased risk of the TOPCAT primary outcome (Hazard ratio{HR} 1.44, 95% confidence intervals {CI} 1.10-1.89, p=0.008), increased risk of HF hospitalizations by 41%(HR 1.41 95% CI 1.04-1.91 p=0.0248) but not CVH (HR 1.18, 95% CI 0.93-1.49, p=..169), but not sudden death (HR 1.40, 95% CI 0.70-2.82, p=0.342) or CV death (HR 1.26, 95% CI 0.84-1.89, p=0.257). Risk of pump failure death (PFD) with BBB was significantly higher in HFpEF subjects without a history of AF (Figure left panel .Kaplan Meier Log rank p=0.0478, HR: 4.22, 95% CI: 0.89 to 19.87, p=0.0689) but not in AF (p=0.138). PFD risk was markedly higher in AF subjects without BBB ( Figure right, Kaplan Meier Log rank p=.0012, HR:7.99, 95% CI:1.80 to 35.41,p = 0.0063) than those with BBB (p=0.91) Conclusion: Ventricular dysynchrony induced by BBB independently worsens HFH risk in HFpEF. Its adverse impact on PFD iis seen in the absence of AF. Increase in PFD risk with AF in HFpEF subjects is most prominent in those with normal intraventricular conduction. Mechanical dyssynchrony induced by BBB may have a role in HFpEF subgroups with preserved atrioventricular filling, leading to these adverse HF outcomes

Abstract 4125157: Efficacy of Adding Sodium-Glucose Co-Transporter 2 Inhibitor versus Standard Therapy Alone in Post-Percutaneous Coronary Intervention Patients: A Systematic Review and Meta-Analysis

Background: Recent evidence suggests that sodium-glucose cotransporter-2 inhibitors (SGLT2-i) may improve outcomes in patients with coronary artery disease (CAD) through various physiological pathways. However, their impact on patients who have undergone percutaneous coronary intervention (PCI) is not well established. This meta-analysis aims to evaluate the effectiveness of additive SGLT2 inhibitors versus standard therapy alone in patients with CAD after PCI. Methods: A systematic search was conducted across the Medline, Embase, and Cochrane Library databases for randomized controlled trials (RCTs) and observational studies that compared the addition of SGLT2 inhibitors to standard therapy versus standard therapy alone in patients post-PCI. The outcomes analyzed were Major Adverse Cardiovascular Events (MACE), all-cause death, cardiovascular death, recurrent acute myocardial infarction (AMI), nonfatal stroke, revascularization, and hospitalization for heart failure (HF). Results: A total of 7 studies met the inclusion criteria, encompassing a total of 11,800 individuals (5,004 on SGLT2-i and 6,796 non-SGLT2-i; mean age of 62.7 years; 28% women; 95% diabetic patients). SGLT2 inhibitors significantly reduced the risk of all-cause mortality (RR 0.6, 95% CI: 0.5-0.72, p&lt;0.01), cardiovascular death (RR 0.39, 95% CI: 0.16-0.94, p=0.03) and hospitalization for HF (RR 0.55, 95% CI: 0.4-0.76, p&lt;0.01) compared to standard therapy alone. The occurrence of the composite endpoint (MACE) (RR 0.67, 95% CI: 0.44-1.01, p=0.056), any revascularization (RR 0.93, 95% CI: 0.57-1.53, p=0.784), recurrent AMI (RR 0.70, 95% CI: 0.41-1.18, p=0.176) and stroke (RR 0.94, 95% CI: 0.68-1.30, p=0.717) did not differ significantly between groups. Conclusions: Adding SGLT2 inhibitors to standard therapy significantly improved cardiovascular outcomes in patients with CAD who have undergone PCI, including reduced mortality and hospitalization for HF rates, with similar rates of recurrent AMI, coronary revascularization and stroke. These findings support the consideration of adding SGLT2 inhibitors as part of the therapeutic regimen for post-angioplasty patients, especially those with diabetes.

Abstract 4117834: Utility of Abdominal Aortic Calcification Assessment for the Prediction of Major Adverse Cardiovascular Events in Liver Transplant Patients

Background: Cardiovascular disease is a leading cause of postoperative morbidity and mortality following liver transplantation (LT). Presence of abdominal aortic calcification (AAC) has been linked to cardiovascular events in the general population. We investigated whether AAC on pre-transplant computed tomography (CT) predicts major adverse cardiovascular events (MACE) post-LT. Methods: Consecutive LT patients between 2010-2018 from the Victorian Liver Transplant Unit (Australia) were included. Extent of AAC was quantified in a blinded fashion, with high AAC defined as a calcium score of ≥500. MACE was defined as any recorded episodes of acute coronary syndrome (ACS), ventricular arrhythmia, decompensated heart failure, or stroke. The primary outcome was post-LT MACE at 30 days and the secondary outcome was all-cause mortality at maximal follow-up. Results: Of 461 patients undergoing LT, 350 had suitable CTs for analysis, of which 90 (25.7%) had also undergone CT coronary angiography. High AAC was identified in 98 patients (28.0%). This finding demonstrated a moderate correlation with high coronary artery calcium score (CACS) ≥400 (r=0.52, p&lt;0.001). Fifty-eight MACE occurred in 42 patients (12.0%) within 30-days. High AAC was associated with increased risk of 30-day MACE (OR=2.68 (95%CI 1.39-5.17), p=0.004), and long-term mortality (HR=2.52 (95%CI 1.29-4.92), p=0.007) at a median follow-up of 4.0 years. In addition, high AAC predicted an increased risk of ACS (OR 3.80 (95%CI 1.18-12.27), p=0.025), heart failure (OR 3.07 (95%CI 1.21-7.80), p=0.020) and atrial fibrillation (OR 2.04 (95%CI 1.02-4.07), p=0.048), with a trend to increased prevalence of ventricular arrhythmia (OR 2.67 (95%CI 0.84-8.50), p=0.10). Following multivariate analysis, high AAC remained a strong independent predictor of MACE (OR=3.49, 95%CI 1.21-10.06, p=0.021). Addition of AAC to the revised cardiac risk index (RCRI) improved model fit for predicting MACE (net reclassification improvement of 52.7% (p&lt;0.001)). Conclusions: This study demonstrates for the first time that high AAC on routine abdominal CT scans is associated with a 3-fold increased risk of 30-day MACE post-LT, and improves cardiovascular risk prediction compared to traditional risk scores. Quantification of AAC may offer a simple method of improving cardiovascular risk assessment and implementation of preventative strategies in liver transplant patients, using pre-existing scans without additional cost or patient risk.

Abstract 4138718: Teen Pregnancy and Risk of Premature Major Adverse Cardiovascular Events

Introduction: Teen pregnancy (TP), defined as pregnancy between 10 and 19 years, is associated with adverse pregnancy outcomes and perpetuates socioeconomic disadvantage, but the impact in later life is not well studied. We investigated the association of TP with premature major adverse cardiovascular events (PMACE) Methods: We used data from the National Health and Nutrition Examination Survey 1999–2018. Surveys were linked with the National Death Index to ascertain mortality records. Only adult females aged 20 years and older were included in the analysis. Participants were divided into 3 groups based on age at their first life birth: 19 or younger (TP), 20 and above (non-TP), and nulliparous women (NP). TP was ascertained by age at first life birth ≤ 19 years, and PMACE was defined as any self-reported diagnosis of coronary artery disease, stroke, heart failure, or all-cause mortality occurring before age 65. We assessed the association between these groups and PMACE using univariate and multivariate logistic regression models. Result: Among 19,737 (weighted frequency of 83,450,668) adult females, 24.2% had a history of TP, 54.3% had a history of non-TP and 21.5% were NP. Compared with NP females, females with TP had a higher odd of PMACE with an unadjusted odd ratio of 3.75 (95%CI, 2.80 - 5.01) versus 2.07 (1.55 – 2.75) among non-TP. Adjusting for age, race, alcohol use, smoking, and social determinants of health factors such as income, educational status, insurance status, and food insecurity, TP remained independently associated with higher odds of PMACE with an adjusted odd ratio of 1.66 (95%CI, 1.19 – 2.30); p=0.003, but this association was not statistically significant among non-TP females with aOR 1.32 (0.95 – 1.84); p=0.10. Conclusion: Teen pregnancy was associated with higher likelihood of PMACE. This association may be indicative of the enduring impact of social determinants of health factors associated with teen pregnancy into adulthood.

Abstract 4125025: Association between Marital Status and Major Adverse Cardiovascular Events: Role of Stress-Related Neural-Immune Mechanisms

Background: Chronic stress is associated with cardiovascular disease (CVD) in part through neural mechanisms that potentiate inflammation. Disrupted social connections are associated with higher chronic stress. As such, we hypothesized that: 1) previously married (divorced, separated) individuals have higher major adverse cardiovascular event (MACE) risk compared to married individuals and 2) that greater activation of stress-related neural-immune mechanisms contributes to this relationship. Methods: Participants (N=75,638) enrolled in the Mass General Brigham Biobank were studied. Marital status and MACE were identified using survey data and ICD-10 codes, respectively. A subset (N=1,121) underwent clinical 18 F-FDG-PET imaging, enabling assessment of stress-related neural activity as the ratio of the amygdala to prefrontal cortex activity (AmygAc). Clinical high-sensitivity C-reactive protein (hs-CRP) levels were assessed in another subset of the cohort (N=10,358). Linear and Cox regression and mediation analyses were used. Results: Among participants (median age 62 years; 53% female), 2,978 subjects developed MACE after Biobank enrollment. Previously married (vs. currently married) individuals had greater MACE risk (HR 1.33 [95% CI: 1.20,1.57], p=&lt;0.001, Figure 1A ) , higher AmygAc (B=0.23 [95% CI: 0.06-0.40], p=0.009) and higher hs-CRP (B=0.19 [95% CI: 0.13-0.25], p=&lt;0.001). MACE risk remained significant after adjustment for key confounders ( Table 1 ), and both the AmygAc and CRP were higher among divorced or separated individuals ( Figure 1B and 1C ). Moreover, increased AmygAc and hs-CRP associated with increased MACE risk (HR=1.24 [1.14-1.36], p=&lt;0.001 and 1.13 [1.09-1.16], p=&lt;0.001, respectively), and both AmygAc and hs-CRP mediated the relationship between marital status and MACE (p&lt;0.05). Conclusions: Our findings suggest that divorced and separated individuals are at an increased risk for MACE. This relationship appears to be driven in part by stress-related neural-immune mechanisms.

Abstract 4125093: Association of Systemic Inflammatory Index and Systemic Inflammatory Response Index with Major Adverse Cardiovascular Events in Patients with Acute Coronary Syndrome Who Had Primary Percutaneous Coronary Intervention

Introduction: Inflammation plays an important role in the pathogenesis of coronary artery disease and Acute Coronary Syndrome (ACS). Inflammatory indicators such as neutrophil count and monocyte count potentially may predict patients’ outcomes and prognosis in ACS. White blood cells count is an affordable and accessible way to assess the systemic immune response. Considering their multidirectional effect on atherosclerosis, new inflammatory biomarkers integrating various leukocyte subgroups have been proposed to calculate the systemic inflammatory response index (SIRI) and systemic inflammatory index (SII). Aim: The aim of this study was to assess the association between the systemic inflammatory response index (SIRI) and Systemic inflammatory index (SII) at admission with major adverse cardiovascular events (MACE) 30-days after Primary Percutaneous Coronary Intervention (PPCI) among patients with Acute Coronary Syndrome (ACS) at one referral hospital in Jordan. Method: A Prospective design was used to assess and follow 150 adults presented with ACS and received PPCI at one referral hospital in Jordan. Data was collected from patients and their medical records during hospital stay using a structured data collection form. The MACE was assessed 30-days after PPCI through phone calls with patients and confirmed from medical records. Results: The study included 150 patients with ACS, 82.7% (n= 124) of them were males. The mean age of patients was 57.68 (SD= 11.19) years. Types of ACS include stable angina 5.3% (n=8), unstable angina 24% (n=36), NSTEMI 28.7% (n=43), and STEMI 24% (n=36). All patients had interventional PCI with balloon and stent insertion. The mean of SIRI was 24.45 (SD=25.49) and the mean of SII was 663.30 (SD= 403.75). Rate of MACE as composite outcome 30-days after PPCI as 24.7% (n=37). The most MACE was unplanned repeat revascularization (n=14, 38% of MACE). Significant association between SIRI and SII, and MACE was found SIRI:(Χ 2 (2)&gt; = 12.63, p = 0.001), SII:(Χ 2 (2)&gt; = 4.23, p = 0.03) . Conclusion: The SIRI and SII are inflammatory biomarkers that should be studied as potentially predictors of MACE among patients presented with ACS.

Abstract 4122284: HEART Score Classification of Major Adverse Cardiovascular Events in Patients with Diabetes Mellitus

Introduction: Risk stratifying diabetes mellitus (DM) patients with chest pain in the emergency department (ED) can pose significant challenges because of atypical symptoms, non-specific ECG changes, and elevated baseline troponin levels. This study aims to evaluate HEART Score performance in DM versus non-DM patients. Methods: A prospective observational cohort study included chest pain patients transported by Emergency Medical Services to University of Pittsburgh Medical Center-affiliated hospitals. Data collection involved extracting data from electronic health records, including both DM and non-DM patients with chest pain. The HEART Score was retrospectively calculated by impartial assessors.The primary endpoint was major adverse cardiac events (MACE) within 30 days. This analysis included the classification performance of bivariate comparisons between the HEART Score and ACS outcomes using the area under the receiver-operator characteristic curve (AUC). Results: 4,058 patients were included. 52.7% were male, 42% were white, there was a mean age of 59.24 years (16.13 SD), 28.63% had DM, and 22.1% had MACE. MACE prevalence was 19.7% in non-DM patients and 28% in patients with DM. The AUC demonstrated more robust discriminatory ability of the HEART Score in non-DM (AUC = 0.81) (95% CI 0.79-0.83) versus DM patients (AUC = 0.74) (95% CI 0.71-0.78) (p 0.001). The performance of HEART Score components, including history, age, and risk factors, exhibited better significant predictive capability for MACE in non-DM patients compared to DM patients. Conversely, the HEART-ECG and troponin components were not different between the DM and non-DM groups. The HEART Score demonstrates better performance in White individuals and females when contrasted with males and Black individuals. Nevertheless, these disparities do not reach statistical significance. Conclusion: The HEART Score performs differently in DM versus non-DM patients, with stronger discrimination observed in non-DM individuals. The troponin and ECG components exhibit poorer performance in diabetes mellitus (DM) patients within the context of the HEART Score. This underscores the complexity of risk assessment in DM patients with chest pain and suggests the necessity for further exploration and refinement of risk stratification strategies in this population.

Abstract 4140119: Liver Steatosis and Liver Fibrosis Predict Major Adverse Cardiovascular Events in the CLEAR Outcomes Trial

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD), and progressive stages accompanied by liver fibrosis (LF), have been associated with liver-related and CV complications in middle-aged patients, although data on the latter is limited. Objectives: We evaluated whether liver steatosis (LS) or LF are associated with CV outcomes in a large clinical trial that included patients at high CV risk who were statin intolerant (SI), and if so, whether bempedoic acid (BA) treatment reduces observed increases in CV risk. Methods: CLEAR Outcomes evaluated the efficacy of BA in 13,970 SI patients randomized to BA (180 mg daily) or placebo and followed for a median of 40.6 months. The primary outcome was a 4-component major adverse CV event (MACE4: nonfatal MI, nonfatal stroke, coronary revascularization, or CV death). This post-hoc analysis used the following non-invasive algorithms to estimate the presence of LS and LF at baseline: Framingham Steatosis Index (FSI), Fibrosis-4 Index (FIB-4) and NAFLD Fibrosis Score (NFS). Continuous variables were reported as mean±SD, categorical variables as proportion. Time-to-event data were analysed using a Cox proportional hazards model. Adjusted hazard ratios (aHR) for every 1 unit increase in score, while holding every other variable constant, and corresponding 95% CI were reported. Results: The mean age of included participants was 66±9 years, 48% were female, mean BMI was 30±5 kg/m 2 , and characteristics were balanced over the treatment arms. Baseline FSI was 0.2±1.5, FIB-4 1.3±0.6 and NFS -0.6±1.2. LS was associated with an increased incidence of MACE4 in the whole study population, as indicated by the aHR of 1.09 (1.06-1.12) for 1 unit of FSI increase. LF was also associated with increased risk of MACE4 in the overall population, aHR 1.19 (1.11-1.28) for 1 unit of FIB-4 increase, and aHR 1.14 (1.10-1.19) for 1 unit of NFS increase. For LS, per 1 unit of FSI increase the aHR for MACE4 was lower in the treatment group: aHR of 1.04 (0.99-1.09) for BA vs 1.14 (1.09-1.18) for placebo, interaction p=0.004. For LF, aHR did not differ between groups and no significant interaction with treatment was observed. Conclusion: Both LS and LF are associated with an increased risk of MACE4. Overall, BA was associated with lower rates of MACE4 across categories of LS and LF (data not shown). A lower risk of LS-associated MACE4 was observed in the BA group. These benefits are less clear regarding the MACE4 risk driven by LF.

Incidental Coronary Artery Calcification and the Risk of Major Adverse Cardiovascular Outcomes

Incidental Coronary Artery Calcification and the Risk of Major Adverse Cardiovascular Outcomes

Abstract 4140115: Comparison of Lipoprotein(a) and Other Apo B Containing Lipoproteins as Predictors of Major Adverse Cardiovascular Events in ODYSSEY OUTCOMES

Background: Lipoprotein(a) [Lp(a)] and other atherogenic lipoproteins each contain one molecule of apolipoprotein B (apoB) per particle. Recent studies have suggested that on a per particle basis, Lp(a) is more strongly associated with major adverse cardiovascular events (MACE) than low density lipoprotein. Hypothesis: In statin-treated patients with recent acute coronary syndrome (ACS), we tested the hypothesis that, on a per particle basis, Lp(a) and its change on treatment with alirocumab (ALI) are more strongly associated with MACE than other [non-Lp(a)] apoB-containing particles. Methods: Molar apolipoprotein(a) [corresponding to Lp(a)] and apo B were measured by mass spectrometry at baseline and month 4 (M4) in a subgroup of 11,957 patients who provided consent for use of stored samples in the ODYSSEY OUTCOMES trial. Non-Lp(a) apoB in nmol/L was calculated as total apo B – Lp(a). Lp(a) and non-Lp(a) apo B at baseline in the placebo group, and absolute changes in their levels on ALI, were related to risk of MACE using proportional hazards models. The latter analysis was adjusted for baseline Lp(a) and non-Lp(a) apo B and stratified by baseline Lp(a) (&lt;125 nmol/L and ≥125 nmol/L). Results: Baseline levels of Lp(a) and non-Lp(a) apoB are shown in the Table . In the placebo group, both baseline Lp(a) and non-Lp(a) apo B independently predicted MACE. At M4 in the ALI group, median Lp(a) change from baseline was -40.9 and -7.0 in those with baseline levels ≥ or &lt;125 nmol/L, respectively. Corresponding median changes in non-Lp(a) apoB were -739 and -776 nmol/L (all P&lt;0.001). In the ALI group with baseline Lp(a)&gt;125 nmol/L, the decrease from baseline in Lp(a), but not the decrease in non-Lp(a) apo B, was significantly related to risk of MACE. Among those with baseline Lp(a)≤125 nmol/L, the decrease from baseline in non-Lp(a) apo B, but not in Lp(a), with ALI was significantly related to risk of MACE. Conclusions: On a per particle basis, baseline Lp(a) and non-Lp(a) apo B both predicted MACE. Among those with high baseline Lp(a), reduction in MACE with ALI was predominantly associated with reduction of Lp(a); among those with lower baseline Lp(a) reduction in MACE with ALI was predominantly associated with reduction in non-Lp(a) apo-B. Lp(a) may be an important target of treatment with ALI in those with elevated levels after ACS.

Abstract 4137424: Circulating Levels of the Pro-Fibrotic Collagen Hormone Endotrophin are Associated with the Risk of Experiencing Major Adverse Cardiovascular Events in Individuals with Type 2 Diabetes – The Thousand&amp;2 Study

Introduction: Cardiovascular disease (CVD) complications are the leading cause of mortality in individuals with type 2 diabetes (T2D). Abnormal extracellular matrix (ECM) remodelling leads to the release of ECM protein fragments into circulation, reflecting these complications. Endotrophin, a pro-fibrotic and -inflammatory hormone, released during collagen type 6 formation, has been linked to adverse outcomes in T2D, but not previously in a long-term perspective. Aim: To assess the 12-year prognostic value of circulating endotrophin levels, measured by PRO-C6, to predict the risk of major adverse cardiovascular events (MACE) in a large cohort of individuals with T2D. Methods: Endotrophin levels were measured with the NordicPRO-C6™ ELISA in 909 serum samples from the Thousand&amp;2 study, which was initiated in 2011 and examined individuals with T2D, with and without known CVD. Clinical data were collected at baseline. Follow-up was 100% complete and performed on the 1 st of May 2024 with the registration of data on MACE from the Danish national registers. The primary outcome was MACE, defined as incident events of hospital admission for ischemic heart disease, heart failure, stroke, or all-cause mortality. PRO-C6 was split into tertiles and examined for survival probability by Kaplan-Meier analysis. Univariate Cox proportional hazard regression analysis was conducted to examine the association between PRO-C6 and the risk of MACE. A multivariable Cox model was additionally conducted, adjusted for age at baseline, sex, systolic blood pressure, duration of diabetes, HbA1c, estimated glomerular filtration rate, use of statins, albuminuria status, and current or prior smoking. Results: The baseline mean (±SD) age of the cohort was 64 (±10) years, 66% were males, mean (±SD) PRO-C6 was 11.9 (±7.01) ng/ml, the median follow-up time was 10.6 years, and number of MACE recorded was 472. The risk of experiencing MACE was significantly higher in the third tertile compared to the first and second tertile (Log-Rank p &lt; 0.001). In the univariate Cox model, the estimated hazard ratio (HR), corresponding to a 2-fold increase of PRO-C6, was HR [95% Confidence Interval(CI)] = 2.1 [1.8-2.4], P &lt;0.001. In the fully adjusted Cox model, PRO-C6 remained significantly associated with the risk of MACE (HR [95% CI] = 1.5 [1.2-1.8], P &lt;0.001). Conclusion: Elevated circulating endotrophin is associated with MACE in T2D, independent of common risk factors.

Abstract 4138246: Differences in Major Adverse Cardiovascular and Lower Limb Events and Guideline-Directed Medical Therapy Among Males and Females Within an Integrated Healthcare System

Background: Health disparities based on gender have been recognized as having a detrimental impact on care delivery and early identification of disease processes. Peripheral arterial disease (PAD) is the third leading cause of atherosclerotic disease mortality. It is unclear what role, if any, gender plays in the diagnosis, treatment, and outcomes of PAD. Hypotheses: Females are less likely to have guideline-directed medical therapy (GDMT) and more likely to have major adverse cardiovascular events (MACE) and major adverse lower limb events (MALE) than males. Methods: The Intermountain Health electronic database was queried for patients meeting the following criteria: ≥18-years of age, PAD diagnosis between Jan 2006 to Dec 2021, seen at least once within the 18-months following initial PAD diagnosis, and had a symptom of PAD (see table). Follow-up GDMT, based on the 2016 AHA/ACC PAD guidelines, was determined by medication and procedures. Time to outcomes of MACE (all-cause death, MI, stroke, or unstable angina hospitalization) and MALE (limb ischemia, limb revascularization, or limb amputation) were examined using Cox-proportional hazard adjusted for GDMT, age, and prior CAD. Results: A total of 7522 patients had a symptomatic PAD diagnosis, with 38% female and 62% male. Females tended to be older (70.1±13.0 vs 68.6±11.7), more likely to be obese (25% v 21%), and less likely to have Afib (21% v. 24%), CAD (30% v 41%), MI (11% v 16%), renal failure (19% v 22%) but more likely to have a bleeding history (30% v 26%) (all p&lt;0.01). Females were slightly less likely to have all the GDMT and yet had similar rates of referrals to specialists but higher rates to primary care providers (Table). After adjustment, females were less likely to have MACE (HR=0.94; 95% CI: 0.88, 0.99) and MALE (HR=0.85; 95% CI: 0.80, 0.92). Conclusion: Females had lower rates of MALE, driven by lower limb revascularization or amputation rates, and slightly lower rates, after adjustment, for MACE. This was observed despite the high rates of GDMT for both females and males (~80% in any category), with females having slightly less GDMT.

A Meta-analysis of the Risk of Adverse Cardiovascular Events in Patients with Cancer Treated with Inhibitors of the PI3K/AKT/mTOR Signaling Pathway.

With the increasing of PI3K/AKT/mTOR (PAM) inhibitors in cancer therapy, there is a growing need to understand the incidence of cardiovascular events (CVAEs) associated with PAM inhibitors. A systematic search of all randomized clinical trials (RCTs) containing at least one PAM group in electronic databases such as PubMed, ClinicalTrials.gov registry, Embase, Medline, Cochrane Library, and major conferences was performed to extract available CVAEs. The cut-off date was January 31, 2024. Study heterogeneity was assessed using the I2 statistic. The risk of CVAEs associated with PAM inhibitors was calculated using Peto OR. The primary outcome was the incidence (95% CI) of PAM inhibitors cardiovascular adverse events in the total population and subgroups. The secondary outcome was the pooled risk of different CVAEs associated with PAM inhibitor exposure in the RCTs. 33 unique RCTs (n = 12,351) were included. The incidence of PAM inhibitors CVAEs of any grade in the intervention group was 48.2%, yielding a combined OR of 2.52 (95% CI 1.82-3.49). The incidence of severe adverse cardiovascular events (≥ grade 3) in the intervention group was estimated at 7.1%, yielding a combined Peto OR of 1.41 (95% CI 1.04-1.93). PAM inhibitors were associated with an increased risk of 5 CVAEs including peripheral edema, lymphoedema, hypercholesterolemia, hypertriglyceridaemia and hyperlipidemia, with higher risks for hypercholesterolemia (Peto OR: 3.27,95% CI 2.61-4.11, P < 0.01; I2 = 55.5%, P = 0.06) and hyperlipidemia (Peto OR: 3.53. 95% CI 1.70-7.32, P < 0.01; I2 = 19.3%, P = 0.29). This study identified an overall incidence of PAM inhibitors CVAEs and the increased risks associated with PAM inhibitor for five specific CVAEs, not confined to hypercholesterolemia and peripheral edema.

Upadacitinib and Cardiovascular Adverse Events in Rheumatoid Arthritis: A Systematic Review and Meta-Analysis.

Upadacitinib, a Janus kinase (JAK) inhibitor used in rheumatoid arthritis treatment, has prompted safety concerns due to potential cardiovascular adverse events. However, current evidence does not provide a definitive conclusion. We conducted a comprehensive systematic review of the literature up until March 15, 2024, utilizing databases like PubMed/Medline, Embase, and Cochrane CENTRAL. A meta-analysis approach was used to derive pooled odds ratios (OR) along with their 95% confidence intervals (CI) to assess the cardiovascular risk associated with upadacitinib. Publication bias was evaluated using Begg's and Egger's tests. Our meta-analysis included six studies with a total of 4,202 participants. For the 15 mg dosage of Upadacitinib, the pooled OR was 1.20 (95% CI: 0.3-4.3), indicating a nominal, non-significant increase in the risk of cardiovascular adverse events. Analysis of the 30 mg dosage presented a pooled OR of 2.37 (95% CI: 0.6-9.1), pointing to a higher, yet statistically insignificant, potential risk. The absence of publication bias was confirmed through Begg's and Egger's tests. The analysis suggests a potential heightened cardiovascular risk associated with Upadacitinib, more so with the 30 mg dosage. Nevertheless, the lack of statistical significance and the wide confidence intervals necessitate a prudent approach to these findings. Tailored treatment strategies, rigorous monitoring, and further empirical studies are crucial for refining the safety profile of upadacitinib and ensuring optimal patient outcomes.

Risk of Major Adverse Cardiovascular Outcomes in Families With MASLD: A Population-Based Multigenerational Cohort Study.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a risk factor for cardiovascular disease. However, whether family members of individuals with MASLD also share an increased cardiovascular risk is unknown. We created a nationwide multigenerational cohort study identifying all family members of Swedish adults diagnosed with biopsy-proven MASLD (1969-2017) and of matched general population comparators (by age, sex, calendar year, and county of residence). We calculated incidence rates and used Cox models to calculate adjusted hazard ratios (aHRs) and 95% CIs for incident major adverse cardiovascular events (MACE), including acute myocardial infarction, stroke, hospitalization for heart failure, or cardiovascular death. Cox models were adjusted for education, country of birth, diabetes, hypertension, obesity, dyslipidemia, chronic kidney disease, chronic obstructive pulmonary disease, and the Charlson comorbidity index. We identified 22 267 MASLD first-degree relatives (FDRs; parents, siblings, and offspring) and 5687 MASLD spouses, as well as 118 056 comparator FDRs and 29 389 comparator spouses without earlier cardiovascular disease. Overall, the mean age was 41.8 years (SD, 18.0), and 51.5% were females. Over a median of 24.6 years, the incidence rate for MACE was higher in MASLD FDRs than in comparator FDRs (65.0 versus 62.5/10 000 person-years; aHR, 1.06 [95% CI, 1.01-1.11]). MASLD FDRs had higher rates of acute myocardial infarction (23.0 versus 20.9/10 000 person-years; aHR, 1.09 [95% CI, 1.01-1.18]) and cardiovascular death (aHR, 1.09 [95% CI, 1.01-1.18]). Across generations of FDRs, the risk of MACE was uniformly increased with no differences by relationship (ie, parents, siblings, and offspring; Pinteraction>0.05). MASLD spouses were also at an increased risk of MACE (117.6 versus 103.5/10 000 person-years; aHR, 1.09 [95% CI, 1.01-1.18]). First-degree relatives of individuals with biopsy-proven MASLD are at slightly higher risk of incident MACE, but absolute risks do not support early screening for cardiovascular disease. Shared lifestyle factors may be the main contributors, as spouses of MASLD patients also had higher risks of MACE.