Cardiovascular Disease Events Research Articles

Cost-Effectiveness of Salt Substitution and Antihypertensive Drug Treatment in Chinese Prehypertensive Adults.

Recent guidelines recommend antihypertensive drug treatment for prehypertensive individuals with blood pressure between 130/80 and 139/89 mm Hg. This study evaluates the cost-effectiveness of 3 interventions in Chinese prehypertensive adults: salt substitution, antihypertensive drug treatment, and their combination. We developed a Markov cohort model to estimate cardiovascular disease (CVD) events, costs, and quality-adjusted life years (QALYs) over a lifetime. Data from the China Kadoorie Biobank informed the simulation. Costs and utilities were drawn from published sources. We evaluated the cost-effectiveness of salt substitution alone, antihypertensive drug treatment alone, and a combination of the 2, focusing on the overall prehypertensive population, those at high CVD risk, and different starting ages (40, 50, 60, and 70 years). Incremental cost-effectiveness ratios (ICERs) were calculated per QALY gained. Salt substitution at age 40 years is the only cost-effective strategy for prehypertensive individuals, with an ICER of $6413.62/QALY. For those at high CVD risk, the combination intervention starting at age 40 years is most cost-effective, with an ICER of $2913.30/QALY. Interventions initiated at younger ages yielded greater CVD reductions and lower ICERs. For example, a combined intervention at age 40 years reduces CVD events by 5.3% with an ICER of $2913.30/QALY, compared with 4.9% and $32 635.33/QALY at age 70 years. These results were consistent across sensitivity analyses. In China, replacing usual salt with a salt substitute is more cost-effective than treating prehypertensive individuals over the age of 40 years with antihypertensive drugs. Furthermore, starting intervention at a younger age in prehypertensive adults can result in even greater cost savings.

Cost-effectiveness analysis of implementing the Nagasaki Acute Myocardial Infarction (AMI) secondary prevention clinical pathway

Abstract Background/Introduction Because of the poor prognosis associated with acute coronary syndromes (ACS), intensive low-density lipoprotein cholesterol (LDL-C) management therapy is recommended as early as possible after the onset of ACS, with the goal of lowering plasma LDL-C to <70 mg/dL. In Nagasaki City, a council was formed comprising all hospitals performing percutaneous coronary intervention along with general physicians, and an initiative to manage LDL-C using a region-wide LDL-C management clinical pathway (Figure 1) was launched in July 2022. The rate of intensive statin therapy at discharge increased from 34.5% to 79.8%, and the rate of patients achieving LDL-C <70 mg/dL at discharge increased from 37.2% to 54.6% following the implementation of the clinical pathway. However, the cost-effectiveness of implementing the clinical pathway remains to be determined. Purpose: The purpose of this study was to evaluate the cost-effectiveness of implementing the Nagasaki AMI Secondary Prevention Clinical Pathway. Methods: To evaluate the cost-effectiveness of implementing the clinical pathway compared with no implementation, a lifetime simulation was performed using mathematical models. The models consisted of a decision tree model to model the flow of the clinical pathway (Figure 2) and a Markov model to consider the risks of developing cardiovascular disease (CVD) events. The quality-adjusted life year (QALY) was used as the outcome. Drug costs and treatment costs for each CVD event were included. Drug costs were calculated from actual prescriptions. Treatment costs and utility scores for each event were based on the literature. The risk of each CVD event was calculated using baseline risks estimated using commercial claims data (DeSC Healthcare, Inc.) and patients' LDL-C levels at discharge and 1 month after discharge. LDL-C levels at each time point were set separately for the groups that achieved or did not achieve a discharge LDL-C < 70 mg/dL, for patients with and without implementing the clinical pathway. Results: Implementing the clinical pathway was evaluated as dominant, with an incremental gain of 0.079 QALYs per person and expected cost savings of JPY 103,124 per person. Implementing the clinical pathway was shown to not only provide additional health benefits by preventing CVD, but also to reduce future health care costs. In the analysis with a 10-year time horizon, the result remained dominant, and the same level of cost savings was expected. Conclusions: Implementing the Nagasaki AMI Secondary Prevention Clinical Pathway can be expected to reduce costs, in addition to increasing QALYs by preventing CVD. Further clinical and economic evaluation of long-term follow-up with a collaborative pathway to the general physician after discharge from the hospital is expected.

Mean body mass index during 20 years of follow-up and cardiovascular disease incidence: results from the ATTICA cohort study (2002-2022)

Abstract Background/Introduction The Global Burden of Disease study has estimated that the burden of increased body mass index (BMI) (i.e., approximately >2.000.000 deaths and >70.000.000 disability-adjusted life years) was predominantly dominated by cardiovascular disease (CVD) during 1990–2017. However, the lifelong body weight (BW) status and its relation to CVD risk remains poorly elucidated. Purpose The purpose of this study was to evaluate the relationship between mean BMI during a 20-year period and CVD incidence. Methods Participants initially free-of-CVD from the ATTICA cohort study were used (n=1,348). At baseline and the 10- and 20-year follow-up, CVD events were assessed, according to WHO-ICD-10. Based on three measurements of weight and height, BMI for each measurement was calculated, and, afterwards, the mean BMI during the whole 20-year period was computed. Results During the whole 20-year period, 41% (n=552) of participants consistently had a normal BW, 48% (n=651) had overweight and 11% (n=145) had obesity. The 20-year CVD incidence was: 8.0% (n=44), 14.9% (n=97) and 19.3% (n=28) in those who consistently had a normal BW, overweight and obesity, respectively (p-value<0.001). In multi-adjusted Cox proportional hazards models, adjusted for age, sex, clinical and lifestyle characteristics, compared to participants who consistently had a normal BW, those who had overweight as well as those who had obesity had almost 2 times higher risk to develop CVD during the 20-year period [Hazard Ratio-HR: 1.73, 95%Confidence Interval-CI: 1.13-2.66 and HR: 2.04, 95%CI: 1.11-3.76, for participants with overweight and obesity, respectively]. Conclusion The study findings highlight that, despite the observations of the J-shaped relationship between BMI and all-cause mortality observed in some studies, both overweight and obesity can be significant risk factors for CVD, when lifelong BW status is assessed. Therefore, currently, new lifelong measures are needed to prevent and manage the pervasive overweight and obesity.

Mediterranean-type diet trajectories and 20-year cardiovascular disease incidence: the ATTICA study (2002-2022)

Abstract Background/Introduction The protective effects of the Mediterranean-type diet (MTD) against cardiovascular disease (CVD) are well-known. However, based on a recent systematic review of 57 studies with 1,125,560 participants, MTD adherence has declined worldwide, even in the Mediterranean region, compared to the past, especially in the last decade. Moreover, studies evaluating changes in diet and CVD risk are scarce. Purpose The aim of this study was to longitudinally evaluate MTD adherence and changes in MTD adherence during 20-years of follow-up and its relation to 20-year CVD incidence. Methods Participants initially free-of-CVD from the ATTICA study were used (n=1,986). At 2002 and 2022, CVD events were assessed according to WHO-ICD-10 and MTD adherence was assessed via MedDietScore (range: 0-55). Hence, MTD trajectories were defined according to MTD adherence in 2002 and in 2022 as: low-low, low-high, high-low, high-high (i.e., high: MedDietScore >27/55). Results During the 20-year follow-up, 30.2% (n=600) of the participants were always away (i.e., low-low), 30.0% (n=596) went away (high-low), 21.4% (n=424) were always close (high-high) and 22% got closer (low-high) to the MTD. The 20-year CVD incidence was: 38.8% (n=233), 87.7% (n=321), 10.2% (n=61) and 24.3% (n=103) in those in the low-low, low-high, high-low and high-high trajectory, respectively (p-value<0.001). In multi-adjusted models, adjusted for socio-economic, clinical and lifestyle parameters, it was found that compared to those who were always away from the MTD, those who were always close had 68% lower CVD risk [Hazard Ratio-HR: 0.32, 95%Confidence Interval-CI: 0.14, 0.72], while those who went away during the 20-year follow-up had 47% lower CVD risk [HR: 0.53, 95%CI: 0.32, 0.86]. Conclusion Our study findings highlight the long-lasting effects of the MTD adherence early in the life-course. Public health measures to prevent CVD should focus on facilitating MTD adherence, as early in life as possible.

Estimated impact of inclisiran treatment on hyperlipidemia prevalence and cardiovascular disease events in NHANES dataset

Abstract Background Inclisiran, administered subcutaneously every 6 months, will result in the reduction of LDL-cholesterol levels of approximately 50%. We estimated the eligibility of the US population for Inclisiran treatment and its impact on blood lipids and CVD events. Methods We applied ORION trial eligibility criteria to US adults aged ≥ 18 years in the US NHANES 1999-2018 to estimate the US eligible population. Blood lipid alterations in ORION 10 were applied to estimate the impact on LDL-C levels and hyperlipidemia prevalence in the ASCVD population sample. We also used the Framingham CVD risk scores to estimate 10-year CVD risks in the ASCVD high-risk population sample based on ORION 11. The difference in estimated risks with and without Inclisiran administration, multiplied by the eligible population from NHANES data, represented the potentially preventable CVD events. Results We identified 651 ASCVD persons (projected to 5.55 million) who fit ORION 10 trial eligibility criteria and 359 ASCVD high-risk persons (projected to 2.53 million) who fit ORION 11 trial eligibility criteria for our analysis. We then analyzed the changes in these populations after Inclisiran treatment. Firstly, we estimated that approximately 3.9 million (72.8%) individuals would experience ≥50% LDL-C reductions. Secondly, we estimated that among the ASCVD patients, 5.07 million (91.3%) with elevated LDL-C, 0.25 million (22.8%) with reduced HDL-C, 1.24 million (95.2%) with elevated TC, and 0.65 million (32.4%) with elevated TG would potentially achieve a more reasonable blood lipid level. Finally, among those without CVD, the estimated 10-year CVD risks were 19% before and 13.8% after Inclisiran treatment, reflecting a 5.2% absolute (and 27.4% relative) reduction in risk translating to potentially 130,000 preventable CVD events over 10 years. Conclusion Inclisiran treatment in eligible US adults may substantially reduce hyperlipidemia prevalence and CVD events.core graphics

Healthcare resource utilisation and cost of care of systemic inflammation in individuals with atherosclerotic cardiovascular disease and chronic kidney disease

Abstract Background Atherosclerotic cardiovascular disease (ASCVD) is a chronic disease, progressed by localised or systemic inflammation (SI). Chronic kidney disease (CKD) facilitates the presence of SI and is associated with an increased risk of ASCVD. Previous studies have estimated that 1–2% of the population in Western countries suffer from both conditions. Purpose To investigates the healthcare costs and resource utilisation for individuals diagnosed with ASCVD and CKD, with or without SI. Method The study applied data from the Danish national health and administrative registries from 1994-2022. Patients with ASCVD were identified by ICD-10 codes. CKD was identified by eGFR [15-59mL/min/1.73m2], in the Register of Laboratory Results for Research (RLRR). The latter date of diagnosis of the two diseases were used as index date. CRP-test results were extracted from RLRR. Individuals with conditions associated with CRP-levels and tests observed in association with CVD events or antibiotic/antiviral drug use were excluded. Individuals with at least two valid CRP tests were included. If two CRP-test results ≥2mg/L to <20mg/L were observed less than six month apart, and within two years of index, the individuals were classified to have SI. Individuals diagnosed in the first year of available eGFR were excluded to ensure only incident individuals in the study. Outcomes included costs and use of inpatient (duration ≥12h) and outpatient (<12h) hospital care, cost of primary care and prescription drugs (adjusted to 2022 currency). Results were derived using linear regression models. Results A total of 19,162 individuals’ incident between 2012-2022 were identified – 68% had SI. SI individuals had higher healthcare costs from five years before to three years after index. Individuals generated a total healthcare cost of EUR 69,554 (SI) and EUR 39,540 (no SI) in the study period (difference EUR 30,014, p<0.001). In adjusted analysis, the attributable cost in the three years following index was 1.4 times higher for individuals with SI, compared to individuals with no SI (difference EUR 12,922, p<0.001). Inpatient care accounted for 85% of the cost. SI individuals had significantly more inpatient hospital contacts from four years before to five years after index (7 attributable contacts total, 4.7 attributable contacts after index, 1.2 times more, p<0.001), and more outpatient contacts from five years before to three years after index (6.2 attributable contacts total, 2.3 attributable contacts after index, 1.3 times more, p<0.001). The largest difference was found in the year following index, where the difference was EUR 7,666 (1.5 times higher, p<0.001) cost, 1.5 (1.3 times higher, p<0.001) inpatient hospital contacts, and 1.1 (1.3 times higher, p<0.001) outpatient hospital contacts (adjusted estimates). Conclusion Individuals with SI represent a significant burden to the healthcare system, both in terms of healthcare cost and healthcare resource utilisation.Total healthcare costsAttributable hospital contacts

Advanced biologic therapies are associated with fewer adverse cardiovascular events in patients with inflammatory bowel diseases

Abstract Background Chronic inflammation is an important contributor to the development of atherosclerotic cardiovascular disease (ASCVD) and associated events. Inflammatory Bowel Diseases (IBD) are chronic inflammatory conditions, and meta-analyses of cohort studies demonstrate an increased risk of ASCVD events in IBD patients. Advanced biologic therapies (ABT) targeting the immune system revolutionized treatment of IBD patients but the impact of these therapies on ASCVD events is not known. Purpose To investigate the impact of ABT on ASVCD events in IBD patients. Methods A retrospective cohort study was performed using the TriNetX Diamond Network, a multi-institutional database providing real-time access to de-identified electronic health records, with data updated on 02/14/2024. ABT were defined as one or more the following: infliximab, adalimumab, golimumab, certolizumab pegol, ustekinumab, risankizumab, vedolizumab, or natalizumab. ASCVD events were based on ICD codes for ischemic heart, cerebrovascular, and peripheral vascular diseases. Individuals >40 years with IBD were included. ASCVD events in (1) patients on ABT and (2) patients not on ABT (NABT) were compared. Propensity score matching was performed on sex, aspirin use, and the following ASCVD risk factors: age, hypertension, hyperlipidemia, tobacco use, and type 2 diabetes mellitus. Results This study includes 72,650 individuals in each of the two matched cohorts. There were no differences in baseline characteristics between the two propensity-score matched cohorts (Table). The probabilities of experiencing any ASCVD event at one, three, and five years in the ABT group were all significantly lower than in the NABT group (8.3% vs. 12.4%, OR 0.64; 13% vs. 18.6%, OR 0.66; and 15% vs. 21.2%, OR 0.65; respectively, all p<0.01). Similarly, the probability of experiencing an ischemic heart disease event at one, three, and five years in the ABT group were all significantly lower than in the NABT group (5.2% vs. 7.9%, OR 0.64; 8% vs. 11.7%, OR 0.66; and 9.2% vs. 13.4% OR 0.66; respectively, all p<0.01). The probability of cerebrovascular disease events at one, three, and five years in the ABT group were all significantly lower than in the NABT group (2% vs. 3.3%, OR 0.59; 3.5% vs. 5.7%, OR 0.59; and 4.2% vs. 6.8% OR 0.60; respectively, all p<0.01) and the probability of a peripheral artery disease event at one, three, and five years in the ABT group were also all significantly lower than in the NABT group event (2.8% vs. 4.5%, OR 0.62; 5.1% vs. 7.6%, OR 0.65; and 6.2% vs. 9.3% OR 0.65; respectively, all p<0.01). Conclusions ABT are associated with significantly fewer ASCVD events in the IBD patient population. Future studies examining the differential benefit of drug subclasses on ASCVD outcomes and mechanisms responsible for the ABT benefit, as well as prospective study designs have the potential to identify new therapeutic targets in IBD patients and with applicability beyond IBD patients.Table

Contemporary LDL-cholesterol management in male and female patients at high-cardiovascular risk: results from the European observational SANTORINI study

Abstract Background Middle aged women have a faster increase in atherosclerotic cardiovascular disease (ASCVD) events than men over time. Undertreatment with guideline-recommended therapy in women may be one of the drivers for this burden. Purpose To compare high- or very high-risk male and female patients regarding contemporary 1-year low-density lipoprotein cholesterol (LDL-C) goal attainment, lipid-lowering therapy (LLT) intensity, and major adverse cardiovascular event (MACE) rate. Methods SANTORINI is an observational, prospective study that enrolled high- and very high-cardiovascular risk patients between March 2020 and Feb 2021, across 623 sites and 14 countries in Europe from primary & secondary care settings, with a further 1-year prospective follow-up. We included all patients with an LDL-C measurement at baseline and 1-year follow up (1yFU) for the current analysis. LDL-C goal attainment was defined separately for high and very-high risk categories according to 2019 ESC/EAS guidelines. Results Overall, 5197 males with a mean age of 65 years, and 2013 females with a mean age 66 years were included. At baseline, male patients had higher prevalence of pre-existing ASCVD (81.6% vs. 63.5%), and a lower prevalence of familial hypercholesterolaemia (8.7% vs. 17.2%) than female patients (Table 1). The proportion of patients reaching LDL-C goal improved from baseline to 1yFU, but was greater in males (22.9% and 33.3%, respectively) than females (16.9% and 24.6%, respectively). Similarly, the proportion of patients receiving no LLT decreased from baseline to 1yFU for both sexes, however, more females than males received no LLT at 1yFU (male: 20.7% to 2.7%; female: 23.9% to 3.9%). High intensity statin use increased for both sexes but was higher for males (22.2% to 27.3%) than for females (15.5% to 19.5%) at 1yFU. By contrast, PCSK9i use at baseline and 1yFU was lower for males (6.6% to 9.3%) than for females (9.8% to 13.4%). Nevertheless, the use of combination LLT at 1yFU was lower among females than males (male: 27.8% to 42.2%; female: 26.7% to 40.2%). During follow-up, MACE-4 was higher in males (5.31/100 patient years [PY]; 95% confidence interval [CI]: 4.68–5.95) than in females (3.63/100PY; 95% CI: 2.79–4.47). Similar results were observed for MACE-3 (Table 2). Conclusions Despite similar guideline recommendations, use of combination LLT and high intensity statin therapy was lower in female patients at high or very high cardiovascular risk than in male patients over one year of follow-up. Accordingly, female patients had lower LDL-C goal attainment both at baseline and at one-year. Nevertheless, due to intrinsic risk factors, female patients had lower rates of MACE-4 and MACE-3 than male patients.

Red cell distribution width as a predictor of cardiovascular events in high-risk patients with statin intolerance: post-hoc analysis of the CLEAR Outcomes trial

Abstract Background Despite optimal lipid-lowering therapy there is up to 70% residual risk of recurrent atherosclerotic cardiovascular disease (ASCVD) events, motivating further testing of alternative risk factors and disease pathways. Red cell distribution width (RDW) is a simple and reproducible marker of heterogeneity of cell size in the peripheral blood. High RDW is associated with an increased risk of ASCVD and death, independent of established risk factors. Recent data suggest no significant impact of PCSK9 inhibitors on hsCRP or RDW. In CLEAR Outcomes, baseline hsCRP predicted risk for future cardiovascular (CV) events and death more strongly than elevated LDL-C. It has been shown that bempedoic acid (BA) reduces hsCRP, but its effects on RDW are unknown. Purpose To analyze the effect of BA on a 4-component composite of incident myocardial infarction, stroke, coronary revascularization, or cardiovascular death (MACE-4) and for CV death by baseline RDW, and to confirm the association of increased RDW with elevated risk of MACE. Methods A total of 13,970 individuals with statin intolerance, with or at high risk for ASCVD, were randomized in the multinational CLEAR Outcomes trial with a median follow up of 3.4 years. Compared to placebo, BA reduced mean LDL-C by 21% and median hsCRP by 22% at 6 months. Quartiles of increasing baseline RDW were assessed as predictors of future adverse events after adjustment for traditional risk factors, hsCRP, and randomized treatment assignment. Results Compared to placebo, BA reduced mean RDW by 0.28% at 6 months and 0.13% at 36 months (p<0.0001). There was a weak positive correlation between hsCRP and RDW at baseline (Figure 1). In the placebo group, higher baseline RDW was associated with an increase in the likelihood of MACE-4 and CV death, and the hazard ratios (HR) associated with a 1% increase in RDW after adjusting for covariates and hsCRP were 1.06 (95% CI 1.02-1.11) and 1.22 (1.15-1.29), respectively. When grouped by quartiles of baseline RDW, compared with a reference group with lowest RDW (<13.7%), there was a notable increase in the risk of MACE-4 and CV death among the higher quartiles in the placebo group (Table 1). Those in the 4th quartile demonstrated a 3-fold increase in the risk of CV death (HR, 3.03, 2.00-4.60). The adjusted HRs (95% CI) for BA vs placebo for MACE-4 were generally lower in individuals with elevated baseline RDW than in those in the first quartile [Q1: RDW≤13.7%; 0.96 (0.79-1.17), Q2: RDW 13.7%-14.4%; 0.81 (0.67-0.97), Q3: RDW 14.4%-15.2%; 0.90 (0.75-1.09), and Q4: RDW>15.2%; 0.84 (0.7-1.01)]. Conclusions In a large randomized controlled clinical trial setting, we confirmed an association between elevated RDW and MACE-4. Compared with placebo, BA demonstrated efficacy in reducing CV risk in patients with moderately increased RDW.Figure 1.Correlation of hsCRP and RDWTable 1.Risk of Outcome by RDW Quartile

Association of cardio-cerebrovascular death with isolated diastolic hypertension: a nationally representative survey of 85, 138 adults

Abstract Background Recently, the 2023 European Society of Hypertension (ESH) guideline for hypertension management include isolated diastolic hypertension (IDH) as a distinct classification. But, studies have yielded inconsistent associations between IDH and cardiovascular disease (CVD) events. Method We obtained data from 85138 participants without CVD and antihypertensive medication use who included in the China Chronic Disease and Risk Factors Surveillance (CCDRFS) project 2010. We extracted data on deaths from any cause, cardiovascular diseases, and stroke during follow up. The hazard ratios (HR) and 95% confidence intervals (CI) for all-cause mortality, cardiovascular mortality, and stroke mortality associated with each blood pressure (BP) group were calculated using Cox proportional hazards models, with the normotension group as the reference. Our analyses were performed with sequential adjustment. In the first step, we carried out unadjusted analyses (model 1). In model 2, we added age, sex, ethnic, location, educational attainment, smoking status, alcohol drinking status, exercise, BMI, high-density-lipoprotein cholesterol, low-density-lipoprotein cholesterol, fasting glucose level as adjustment covariates. Results Overall, 57144 (67.1%) participants had normotension, 3826 (4.5%) participants had IDH, 11013 (12.9%) participants had isolated systolic hypertension (ISH), 13155 (15.5%) participants had systolic and diastolic hypertension (SDH). Compared with normotension, IDH was not statistically associated with a significantly increased risk of all-cause mortality (HR, 1.09 [95% CI, 0.86–1.39], model 2), or cardiovascular mortality (HR, 1.21 [95% CI, 0.74–1.96], model 2). On the contrary, IDH was significantly associated with a modestly higher risk of stroke mortality (HR, 1.84 [95% CI, 1.13–3.00], model 2). IDH was significantly associated with a modestly higher risk of stroke mortality in middle aged and older adults, but not young adults (age <45years). Similar results were obtained for men, while for women the associations between the prevalence of IDH and a higher incidence of stroke mortality were not significant. Stage 1 to stage 3 ISH or SDH were associated with a higher risk for all-cause mortality, cardiovascular mortality, and stroke mortality. Conclusion IDH was associated with an increased risk of stroke mortality among the large nationally representative Chinese population. Intervention for IDH may be effective in reducing the burden of stroke in China.

Lipoprotein(a) metabolomic and proteomic features and atherosclerotic cardiovascular disease in young, asymptomatic adults

Abstract Background Lipoprotein (a) [Lp(a)] is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD) events. Although Lp(a) is a powerful genetic risk factor for ASCVD, the pathways that mediate this risk and the associated metabolomic and proteomic features that capture this risk are unknown. Methods In young, asymptomatic Coronary Artery Risk Development in Young Adults (CARDIA) participants, we defined the relationships between Lp(a) and metabolomic (n=563)/proteomic (n=184) features, derived quantitative Lp(a)-omic scores from these features, and related these quantitative scores to ASCVD phenotypes. Results CARDIA subjects had a mean age of 32 years and a median follow-up of 27 years. In the overall cohort (n=3920), Lp(a) levels at year 7 (Y7) were significantly associated with ASCVD endpoints, including hs-CRP, coronary artery calcification (CAC), death, and incident CHD (Figure 1A). In the subcohort (n=2290) that had measurements of Lp(a), proteomics, and metabolomics, Y7 Lp(a) levels were associated with distinct proteomic and metabolomic features indicative of immune responses, lipoprotein metabolism, atherogenesis, and arginine/steroid biosynthesis. Using machine learning approaches, Lp(a) metabolomic, proteomic, and transomic quantitative scores were derived. After adjustment, the Lp(a) transomic score was more strongly related to incident CAC, degree of CAC, CRP, and incident CHD than Lp(a) itself (Figure 1B). Conclusions To our knowledge, this is the first study to examine the relationship between Lp(a), metabolomic/proteomic features, and ASCVD phenotypes in young, asymptomatic adults. The multi-omics approaches employed here provide insight into the pathobiology of Lp(a)-driven ASCVD and enable more nuanced mechanistic risk assessment compared with Lp(a) alone.

Effect of alirocumab on coronary plaque stratified by atherothrombotic risks

Abstract Background Previous clinical studies have shown that high-risk subgroups including patients with major atherosclerotic cardiovascular disease (ASCVD) events and multiple atherothrombotic risk factors derive enhanced cardiovascular benefit from proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition. To date, the effect of alirocumab on coronary plaque regression stratified by the number of atherothrombotic risk factors remains unknown. Purpose To investigate the utility of atherothrombotic risk stratification to identify patients with acute myocardial infarction (AMI) who have the greatest potential for benefit on plaque regression as assessed by intracoronary imaging from the addition of alirocumab to high-intensity statin therapy. Methods This was a substudy of the PACMAN trial, a randomized, double-blind trial comparing biweekly alirocumab (150 mg) versus placebo in AMI patients undergoing percutaneous coronary intervention. Intravascular ultrasound (IVUS) was serially performed in non-infarct-related coronary arteries at baseline and after 52 weeks. Atherothrombotic risk factors defined in the 2018 ACC/AHA cholesterol guidelines include myocardial infarction, ischemic stroke, peripheral artery disease, age ≥65 years, familial hypercholesterolemia, coronary revascularization, diabetes, hypertension, chronic kidney disease, current smoking, LDL-C ≥100 mg/dL despite maximum tolerated statin therapy, and history of heart failure. The key endpoint was the change in IVUS-derived percent atheroma volume (PAV) from baseline to 52 weeks. Results A total of 263 patients available for serial IVUS data were analyzed for the current study. The most prevalent atherothrombotic risk factors were current smoking (49%), hypertension (43%), and age ≥65 years (24%). Patients were divided into 3 groups according to the number of risk factors (0 risk factor: n=52, 1 risk factor: n=101, ≥2 risk factors: n=100). Patients with risk factors had greater PAV at baseline compared with those with 0 risk factor (39.0% vs. 42.6% vs. 42.8%, P=0.008). The addition of Alirocumab to high-intensity statin therapy demonstrated a significant reduction in PAV among patients with 0 risk factor (-2.66% vs. -1.02%, P=0.009) and those with 1 risk factor (-2.36% vs. -0.76%, P<0.001) (Figure 1). In contrast, patients with ≥2 risk factors had no significant PAV reduction by alirocumab (-1.72% vs. -1.12%, P=0.076, P for interaction=0.009). Conclusions Among AMI patients with no or 1 atherothrombotic risk factor, the addition of alirocumab to high-intensity statin therapy demonstrated greater coronary plaque regression. Patients with fewer risk factors thus appear to be more susceptible for atheroma regression.Change in PAV stratified by risk factors

Interactive effects of outdoor fine particulate matter and metabolic, behavioural, and psychosocial risk factors on cardiovascular disease: analysis of the PURE-China cohort study

Abstract Background Long-term PM2.5 exposure has been associated with an elevated risk of cardiovascular disease (CVD) and its associated risk factors.[1–4] There is a paucity of studies investigating the interactive effects of PM2.5 exposure and a comprehensive list of risk factors including metabolic, behavioural, and psychosocial risk factors on CVD risk.[5] Purpose This study aims to examine the interactive effects of PM2.5 exposure and metabolic, behavioural, and psychosocial risk factors on incident CVD. Methods The Prospective Urban Rural Epidemiology (PURE)-China cohort study is a population-based cohort study recruiting participants aged 35–70 years from 115 communities in 12 provinces of China between 2005 and 2009, and followed up until August 31, 2021.[6] Participants’ metabolic, behavioural, and psychosocial risk factor information was recorded. PM2.5 concentrations were extracted from a 1x1 km2 global model.[7,8] For this analysis, we included participants aged 35–70 years at baseline without a history of CVD, with at least one follow-up visit. The primary outcome was a composite of major cardiovascular events (CVD deaths, myocardial infarction, stroke, and heart failure). Additive interaction was measured by relative excess risk due to interaction (RERI), the proportion of disease attributable to interaction (AP), and the synergy index (SI).[9,10] To comply with the additive interaction method, we classified concentrations of PM2.5 into low and high levels by the median of 3-year average PM2.5 concentration (45.7 μg/m3, IQR: 33.7-74). Cox proportional hazard models were used to assess the associations of metabolic, behavioural, and psychosocial risk factors on incident CVD by PM2.5 concentrations. Results The PURE-China study recruited 47 931 participants, of which 39 329 are eligible for this analysis. During the median follow-up period of 11.9 years (IQR: 9.6-12.6), 1462 and 2155 major CVD events had occurred in the low and high PM2.5 group respectively. There was a synergistic interaction between PM2.5 and the systolic blood pressure (SBP) for CVD: RERI: 0.363, 95% CI: 0.196-0.531; AP: 0.098, 95% CI: 0.081-0.115; SI: 1.155, 95% CI: 1.132-1.177; high LDL cholesterol: RERI: 0.219, 0.003-0.436; AP: 0.135, 0.008-0.263; SI: 1.549, 0.947-2.533. A significant synergistic interaction was also identified between PM2.5 and household air pollution (RERI: 0.457, 0.292-0.622; AP: 0.277, 0.184-0.37; SI: 3.362, 1.409-8.019). Interactions between PM2.5 and low grip strength on CVD were significantly synergistic, but antagonistic between PM2.5 and low physical activity (RERI: -0.248, -0.485--0.012; AP: -0.174, -0.349-0.001; SI: 0.633, 0.412-0.971). Conclusion Addictive interaction was between PM2.5 and SBP, high LDL cholesterol, household air pollution, low grip strength and low physical activity on incident CVD, indicating the benefit of coordinated control strategies for metabolic, physical, and environmental risk factors for the prevention of CVD.

Cardiovascular risk prediction using metabolomic biomarkers and polygenic risk scores: a cohort study and modelling analyses

Abstract Background/Introduction Metabolomic biomarker scores and polygenic risk scores (PRS) have shown promise for improving cardiovascular disease (CVD) prediction, but have not yet been evaluated in the context of current prediction models (SCORE2) and ESC recommendations for 10-year prediction of fatal and non-fatal CVD. Purpose To assess whether metabolomics biomarkers and PRSs can improve 10-year CVD risk prediction when added to SCORE2, and whether improvements are meaningful at ESC 2021 recommended risk thresholds for treatment consideration. Methods Metabolomics biomarker scores were constructed and compared to PRS and SCORE2 in 170,000 UK Biobank participants (5,096 incident CVD cases) aged 40–69 without previous CVD, diabetes, or lipid-lowering treatment. Improvement in risk discrimination when added to SCORE2 was assessed using Harrel’s C-index. Improvement in risk stratification following ESC guideline risk thresholds was assessed using categorical net reclassification. Population modelling was subsequently applied to estimate the impact on CVD prevention if applied at scale. Results Risk discrimination provided by SCORE2 (C-index: 0.718) was similarly improved by addition of metabolomic biomarker scores (ΔC-index: 0.011 [0.009–0.014]) and PRSs (ΔC-index 0.009; [0.007–0.012]). Addition of both metabolomic biomarker scores and PRSs to SCORE2 yielded the largest improvement risk discrimination, with ΔC-index 0.019 (0.016–0.022). Concomitant improvements in risk stratification were observed in categorical net reclassification index, with net case reclassification of 13.04% (11.67–14.41%). Modelling metabolic biomarker scores and PRSs for targeted risk-reclassification increased the number of CVD events prevented per 100,000 screened from 201 to 370 (ΔCVDprevented: 170 [158–182]) while essentially maintaining the number of statins prescribed per CVD event prevented. Conclusions Combining metabolomic biomarker scores and PRSs with SCORE2 moderately enhances prediction of first-onset CVD, and could have substantial population health benefit if applied at scale.

Sleep characteristics in relation to cardiovascular disease incidence and mortality in individuals with diabetes

Abstract Background/Introduction Evidence regarding the potential health effects of sleep characteristics among individuals with type 2 diabetes (T2D) is limited. Purpose We aimed to examine sleep characteristics in relation to subsequent risk of cardiovascular disease (CVD), including coronary heart disease (CHD), and stroke, and all-cause and cause-specific mortality among individuals with T2D. Methods We prospectively followed 21,902 men and women with T2D at baseline or diagnosed during follow-up (Nurses' Health Study: 1986-2018, Health Professionals Follow-Up Study: 1986-2018). Sleep characteristics, including sleep duration, snoring, sleep apnea, and sleep quality, were repeatedly assessed using self-reported questionnaires at baseline and follow-up. Associations of sleep characteristics with CVD risk and mortality were assessed using Cox proportional hazards models with adjustments for demographic, dietary and lifestyle factors, and medical history. Results During 170,355 and 196,458 person-years of follow-up in participants with T2D, there were 2,486 incident CVD events and 3,922 deaths, respectively. Compared with sleeping for 7-8 h/day, the multivariable-adjusted hazard ratios (HRs) of sleeping for ≤5 h/day were 1.21 (1.02, 1.45) for CVD incidence, 1.24 (1.20, 1.51) for CHD incidence, 1.40 (1.24, 1.58) for total mortality, 1.52 (1.20, 1.92) for CVD mortality, and 1.27 (1.01, 1.61) for other non-CVD and non-cancer mortality, while the HRs of ≥10 h/day were 1.42 (1.21, 1.66) for total mortality, and 1.63 (1.20, 2.10) for other non-CVD and non-cancer mortality. Furthermore, compared with participants without habitual snoring, those with habitual snoring had a 21%, 24%, 18%, and 33% higher risk for CVD incidence, CHD incidence, CVD mortality, and total mortality, respectively. Compared with participants without diagnosed sleep apnea, those with sleep apnea had a 27%-58% higher risk for CVD incidence, CVD mortality, and total mortality. In addition, lower habitual sleep quality, including sleep difficulties and restless sleep, was associated with a substantially higher risk of CVD, CHD, or CVD mortality. No associations were observed between sleep characteristics with risk of stroke and cancer mortality in individuals with T2D. Conclusions Short and long sleep durations as well as habitual snoring, sleep apnea, and lower sleep quality were independently associated with higher risks of CVD incidence and mortality, particularly CVD mortality in individuals with T2D.

Influence of orthostatic blood pressure changes on the effects of intensive blood pressure control in patients with type 2 diabetes

Abstract Background Intensive blood pressure (BP) control has been proven to reduce the risks of major cardiovascular diseases (CVD) in patients with type 2 diabetes mellitus (T2DM) (1). Excessive orthostatic BP changes should be fully addressed, given its high prevalence and associations with adverse events among T2DM patients (2-5). However, the benefits of intensive BP control among T2DM patients with significant orthostatic BP changes have been equivocal. Purpose To examine whether orthostatic BP changes modify the efficacy of intensive BP control on CVD outcomes in patients with T2DM. Methods The Action to Control Cardiovascular Risk in Diabetes Blood Pressure trial (ACCORD BP) is a 2×2 factorial designed trial that aimed to evaluate the effects of intensive glycemia and BP control on major CVD events among T2DM patients (6). We enrolled participants with at least one record of orthostatic BP values for analysis. The composite CVD outcome in this study comprised cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalized congestive heart failure. Associations between orthostatic BP changes and the composite CVD outcome and all-cause death, respectively, were presented by restricted cubic spline curves based on multivariable Cox models. We examined if the effects of intensive BP control varied across the orthostatic BP change for the composite CVD outcome and all-cause death. Results Among 4330 participants, 877 (20.3%) experienced episodes of orthostatic hypotension (OH) at baseline or during follow-up. There was no significant difference in the proportions of OH participants between the intensive and standard BP arms. U-shaped associations were observed between orthostatic systolic BP changes and the composite CVD outcome, as well as all-cause mortality (Figure 1). In the standard glycemia arm, intensive BP control was significantly associated with a lower risk of composite CVD outcome (HR 0.76, 95%CI 0.59-0.97). There was a beneficial association of intensive BP control with all-cause mortality without statistical significance (HR 0.85, 95%CI 0.56-1.30). The favorable effect of intensive BP control was not influenced by orthostatic BP changes (P for interaction 0.51 for the composite CVD outcome and 0.97 for all-cause mortality) (Figure 2). Beneficial effects of intensive BP control were not observed for participants in the intensive glycemia arm on the composite CVD outcome (HR 0.99, 95%CI 0.76-1.28) and all-cause mortality (HR 1.19, 0.79-1.80). Conclusion Orthostatic BP changes should not be a barrier to intensive BP control for T2DM patients treated with guideline-recommended standard glycemia control.

Predictors of cardiovascular disease risk: findings from the National Survey of Health and Development Cohort

Abstract Background Cardiovascular disease (CVD) remains a significant cause of mortality and morbidity within the UK. CVDs and all-cause mortality can be predicted with varying levels of certainty with different models. Purpose This study aimed to explore the incremental effect of risk factors and respective biomarkers on CVD events risk estimation models. Methods The National Survey for Health and Development (NSHD) birth cohort study, including 2547 women 2815 men, was used to model relationships between conventional and emerging risk factors and cardiometabolic and vascular outcomes, including myocardial infarction and stroke between 1999 and 2009. Logistic regression or XGBoost (eXtreme Gradient Boosting) models were used to predict the outcomes (myocardial infarction and strokes). Model fit was assessed by comparing predicted and known incident events in a two-by-two error matrix for binary outcomes. Results In a model including both sex and smoking alcohol intake (β = -0.029g; p < 0.05), body mass index (BMI) (β = 0.095 kg/m2; p < 0.05), glycated haemoglobin (HbA1c) (β = 0.033 mmol/mol; p < 0.01) and total cholesterol/high density lipoprotein (TC/HDL) ratio (β = 0.459 mg/dL; p < 0.0001) waist-to-hip ratio (β = 5.632cm; p = 0.05) and waist circumference (β = 0.031cm; p < 0.01) were significant predictors of myocardial infarction. A lower risk was observed among those with higher average alcohol intake, whereas higher risk being observed among those with higher BMI, HbA1c levels, total cholesterol/HDL ratio, waist-to-hip ratio and waist circumference. For stroke, exercising 5+ times (β = -1.47; p < 0.01), systolic blood pressure (SBP) (β = 0.040mmHg; p < 0.001), diastolic blood pressure (DBP) (β = 0.027mmHg; p < 0.001), pulse pressure (β = 0.033mmHg; p < 0.01), triglycerides (β = 0.388; p < 0.05) and total cholesterol/HDL ratio (β = 0.419; p < 0.01) were all significant predictors of stroke. We found that higher values of SBP, DBP, pulse pressure, triglycerides and total cholesterol/HDL ratio were associated with higher risk of stroke, whereas higher levels of physical activity were associated with a lower risk. Additionally, by combining BMI, HbA1c and total cholesterol/HDL ratio to the baseline model it provided the greatest F1 score of all models (0.123) and the greatest precision (6.7%), with a recall of 72.4%. With XGBoost we observed a reduced F1 score from 0.123 to 0.079, although adding information on alcohol intake and waist to hip ratio to this model, as previous analysis indicated great improvements in prediction, the F1 score obtained using the XGBoost increased from to 0.079 to 0.103. Conclusion This research shows that clinical and laboratory measurements play a potentially powerful role in predicting health outcomes when using evidence-based risk calculators. Using large cohorts allows for real-life long-term associations to be explored and quantified with a higher level of certainty for replicability across other populations.

Semaglutide for the secondary prevention of cardiovascular disease in people with overweight or obesity, but without diabetes: a cost-effectiveness analysis

Abstract Background The recently published trial, SELECT (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity) [1], was the first study to demonstrate that the glucagon-like peptide 1 receptor agonist, semaglutide, was superior to placebo in reducing the risk of major cardiovascular events in people with existing cardiovascular disease (CVD) and a body mass index of ≥27kg/m² but without diabetes. Despite the promising clinical benefits, the high cost of the medication has raised concerns about its financial viability and accessibility within healthcare systems. Purpose To explore whether use of semaglutide in addition to standard care (background use of lipid lowering, anti-hypertensive and/or anti-platelet therapies) for the secondary prevention of CVD in people with overweight or obesity is cost effective from the Australian healthcare perspective. Methods A Markov model was developed based on the SELECT trial, to evaluate the clinical outcomes and costs of a hypothetical population treated with semaglutide versus placebo over 20 years. With each annual cycle, subjects were at risk of having non-fatal CVD events (MI or stroke) or dying. Treatment efficacy, transition probabilities, and utilities were derived from the SELECT trial and published literature. Costs were obtained from Australian sources. The cost of semaglutide at a dosage of 2.4 mg/week (in line with SELECT) was estimated to be ~A$80 per week or A$4175 per year. The main outcome of interest was the incremental cost-effectiveness ratio (ICER) in terms of cost per year of life saved (YoLS) and cost per quality-adjusted life year (QALY) gained. All outcomes and costs were discounted by 5% per year. Costs are reported in 2023 Australian dollars (A$). Results Over a 20 year time horizon, treatment of 1000 hypothetical subjects with overweight or obesity and existing CVD with semaglutide compared to placebo prevented 126 non-fatal CVD events and 81 deaths, and yielded an additional 0.46 discounted life years and 0.48 discounted QALYs per person. The difference in total discounted costs was A$43,955 per person. This equated to ICERs of A$99,853 per YoLS and A$96,055 per QALY gained. Conclusions Assuming a willingness-to-pay-threshold of A$50,000 per QALY gained, semaglutide would not be considered cost-effective for the secondary prevention of CVD in people with overweight or obesity in Australia at current prices. A price reduction of 52% to less than A$2000 per year would be required for it to be considered a cost-effective treatment strategy in this setting. Given the modest event rates reported in SELECT, cost-effectiveness is likely to improve if use of semaglutide is targeted to higher risk groups. Moreover, SELECT primarily focused on cardiovascular benefits, however data supporting the impact of semaglutide on a number of other weight-related complications are anticipated and will inform a more holistic understanding of its cost effectiveness.

Defining high risk in the cardiovascular-kidney-metabolic syndrome and associated cardiovascular disease outcomes

Abstract Background The American Heart Association (AHA) recently developed the cardiovascular-kidney-metabolic (CKM) syndrome construct with stages 0-4 to comprehensively characterize the spectrum of cardiovascular disease (CVD) risk [1]. CKM Stage 3 is defined by subclinical CVD or high (≥20%) estimated 10-year CVD risk according to the newly-derived PREVENT models [2]. However, within CKM Stage 3, the burden of subclinical atherosclerosis equivalent to a ≥20% estimated CVD risk, and long-term CVD outcomes associated with CKM Stage 3, are not known. Purpose To (1) characterize the distribution of subclinical atherosclerosis by coronary artery calcium (CAC) according to PREVENT estimated CVD risk categories, and (2) quantify long-term CVD risk associated with CKM Stage 3, in two international cohorts of adults without prior CVD. Methods In participants of the Multi-Ethnic Study of Atherosclerosis (MESA, age 45-84 years) and the Rotterdam Study (age ≥55 years), the burden of CAC was calculated across estimated 10-year CVD risk (low, 0 to <5%; borderline 5 to <7.5%; intermediate, 7.5 to <20%; high, ≥20%). Participants were categorized into CKM stages according to CVD risk factors (body mass index, waist circumference, glycemic status, blood pressure, lipids, kidney function), estimated 10-year CVD risk (by AHA PREVENT model), and presence of CAC. The association of CKM syndrome stage with fatal or nonfatal CVD outcomes was evaluated with covariate-adjusted proportional hazards regression. Results Among 6,123 MESA participants (52% female, mean age 61.4 years) and 1,691 Rotterdam Study participants (46% female, mean age 67.1 years), the distribution of CAC across absolute 10-year CVD risk categories is shown in Figure 1. In high (≥20%) CVD risk adults, CAC score ≥100 was present in 50% of MESA participants and 48% of Rotterdam Study participants. Most participants were classified as CKM Stage 3 (53% in MESA, 83% in Rotterdam). Over a median follow-up of 17.5 years in MESA, CVD events occurred in 5% of CKM Stage 0, 6% of Stage 1, 9% of Stage 2, and 26% of Stage 3 participants. Over a median follow-up of 10.2 years in the Rotterdam Study, CVD events occurred in 0% of CKM Stage 0 and 1, 8% of Stage 2, and 17% of Stage 3 participants (Figure 2). The risk of total CVD was significantly higher in CKM Stage 3 participants relative to CKM Stage 0-2 (MESA: adjusted HR 2.74, 95% CI 2.32, 3.23; Rotterdam: adjusted HR 2.18, 95% CI 1.34, 3.54). Conclusions In an international, multi-ethnic sample of middle-aged adults, adults with high (≥20%) absolute 10-year CVD risk by PREVENT had substantial burden of CAC. Adults in CKM Stage 3 had approximately 2.2- to 2.7-times higher risk for CVD, compared with adults in lower CKM stages. Accounting for estimated CVD risk and burden of cardiovascular, kidney, and metabolic risk factors informs prevention of subclinical and clinical CVD.

Long-term outcomes in women diagnosed with heart failure in connection to delivery

Abstract Background Heart failure (HF) among young patients may be from various causes, often triggered by heightened physical demands like pregnancy. Data regarding outcomes of women diagnosed with HF in conjunction to pregnancy and delivery are varied. There remains a notable gap in understanding the outcomes observed in women diagnosed with heart failure in conjunction with delivery. Also, long-term follow-up studies are crucial to elucidate the impact of pregnancy-associated HF on future cardiovascular. Purpose To study the interplay between pregnancy, HF, and subsequent cardiovascular risk. Method Using the personal identification numbers (PINs) that all individuals in Sweden have enables linkage of data between different registers. Data from the National Patient Register (NPR), Swedish Medical Birth Register (MBR) and the Cause of Death Register were also used. All women 18 to 50 years of age registered in the in MBR in the period 1st January 1997 to 31st December 2019 were included. Women with first-time HF in relation to delivery were identified using the international classification code for diseases (ICD-10) I50, I42, I43 and 090.3 together with co-morbidities. Every patient was compared with 5 controls without HF from the Total Population Register matched on age at delivery and calendar year of delivery. Outcomes: all-cause mortality, and any cardiovascular disease (CVD) diagnosed during the observation time. Results A total of 286 cases and 1,430 controls were included. The prevalence of comorbidities at baseline for both patients and controls was low; congenital heart disease (1.4%, vs. 0%), pulmonary hypertension (1.0% vs. 0%), valvular heart disease (5.9% vs. 0%), myocardial infarction 0.7% vs. 0%), arrhythmia (5.9% vs. 0%), hypertension (6.3 % vs. 0.1%), (all p<0.05). Preeclampsia prior to HF diagnosis had 31% of patients vs. 0.2% of controls (p<0.001). Patients exhibited higher mortality rates at 4.9% during median follow up 9.0 (IQR 5.6-13.0) years vs. 0.3%, median follow up 9.4 (6.2-13.5) years and hazard ratios (HR) for all-cause mortality HR (95% CI) of 18.20 (5.99 - 55.31) (p<0.001) compared to controls. During median follow up of 3.2 (0.0-9.2) years 60.1% of patients were diagnosed with CVD both at in-/out-patient settings compared with 4.1% in controls during 9.4 (5.8-13.5) years of follow up. Comparing patients with controls the HR (95% CI) was 22.24 (16.50 - 29.96) p<0.0001 for CVD diagnosis during follow-up, see Figure 1. Conclusion In conjunction with delivery, and in the years thereafter, women with heart failure diagnosis had more than eighteen times higher risk of mortality than women without heart failure. The risk of CVD event in the heart failure group is highest in conjunction with delivery. Figure 1. Cumulative incidence functions for all-cause mortality, CVD in- or out-patient visit adjusted for death as competing risk, comparing cases with controls.