Composite Of Nonfatal Myocardial Infarction Research Articles

Semaglutide and cardiovascular outcomes in patients with obesity and prevalent heart failure: a prespecified analysis of the SELECT trial

Semaglutide, a GLP-1 receptor agonist, reduces the risk of major adverse cardiovascular events (MACE) in people with overweight or obesity, but the effects of this drug on outcomes in patients with atherosclerotic cardiovascular disease and heart failure are unknown. We report a prespecified analysis of the effect of once-weekly subcutaneous semaglutide 2·4 mg on ischaemic and heart failure cardiovascular outcomes. We aimed to investigate if semaglutide was beneficial in patients with atherosclerotic cardiovascular disease with a history of heart failure compared with placebo; if there was a difference in outcome in patients designated as having heart failure with preserved ejection fraction compared with heart failure with reduced ejection fraction; and if the efficacy and safety of semaglutide in patients with heart failure was related to baseline characteristics or subtype of heart failure. The SELECT trial was a randomised, double-blind, multicentre, placebo-controlled, event-driven phase 3 trial in 41 countries. Adults aged 45 years and older, with a BMI of 27 kg/m2 or greater and established cardiovascular disease were eligible for the study. Patients were randomly assigned (1:1) with a block size of four using an interactive web response system in a double-blind manner to escalating doses of once-weekly subcutaneous semaglutide over 16 weeks to a target dose of 2·4 mg, or placebo. In a prespecified analysis, we examined the effect of semaglutide compared with placebo in patients with and without a history of heart failure at enrolment, subclassified as heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, or unclassified heart failure. Endpoints comprised MACE (a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death); a composite heart failure outcome (cardiovascular death or hospitalisation or urgent hospital visit for heart failure); cardiovascular death; and all-cause death. The study is registered with ClinicalTrials.gov, NCT03574597. Between Oct 31, 2018, and March 31, 2021, 17 604 patients with a mean age of 61·6 years (SD 8·9) and a mean BMI of 33·4 kg/m2 (5·0) were randomly assigned to receive semaglutide (8803 [50·0%] patients) or placebo (8801 [50·0%] patients). 4286 (24·3%) of 17 604 patients had a history of investigator-defined heart failure at enrolment: 2273 (53·0%) of 4286 patients had heart failure with preserved ejection fraction, 1347 (31·4%) had heart failure with reduced ejection fraction, and 666 (15·5%) had unclassified heart failure. Baseline characteristics were similar between patients with and without heart failure. Patients with heart failure had a higher incidence of clinical events. Semaglutide improved all outcome measures in patients with heart failure at random assignment compared with those without heart failure (hazard ratio [HR] 0·72, 95% CI 0·60-0·87 for MACE; 0·79, 0·64-0·98 for the heart failure composite endpoint; 0·76, 0·59-0·97 for cardiovascular death; and 0·81, 0·66-1·00 for all-cause death; all pinteraction>0·19). Treatment with semaglutide resulted in improved outcomes in both the heart failure with reduced ejection fraction (HR 0·65, 95% CI 0·49-0·87 for MACE; 0·79, 0·58-1·08 for the composite heart failure endpoint) and heart failure with preserved ejection fraction groups (0·69, 0·51-0·91 for MACE; 0·75, 0·52-1·07 for the composite heart failure endpoint), although patients with heart failure with reduced ejection fraction had higher absolute event rates than those with heart failure with preserved ejection fraction. For MACE and the heart failure composite, there were no significant differences in benefits across baseline age, sex, BMI, New York Heart Association status, and diuretic use. Serious adverse events were less frequent with semaglutide versus placebo, regardless of heart failure subtype. In patients with atherosclerotic cardiovascular diease and overweight or obesity, treatment with semaglutide 2·4 mg reduced MACE and composite heart failure endpoints compared with placebo in those with and without clinical heart failure, regardless of heart failure subtype. Our findings could facilitate prescribing and result in improved clinical outcomes for this patient group. Novo Nordisk.

Efficacy of Aspirin for primary prevention among adults with high-risk type 2 diabetes in the ACCORD trial.

To assess the efficacy of aspirin use for primary prevention of cardiovascular disease (CVD) with incident atherosclerotic CVD and mortality in high-risk type 2 diabetes. In this post hoc analysis, we included participants in the ACCORD trial without CVD at baseline. The association between aspirin use and the primary outcome (a composite of nonfatal myocardial infarction, nonfatal stroke or cardiovascular [CV] death) and all-cause mortality was evaluated using Cox proportional hazard analysis adjusting for demographics, CV risk factors and comorbidities. Eligible participants (n = 6330) were aged 62.8 ± 5.9 years at baseline, 43.8% of the participants were female, and 3026 (47.8%) used aspirin. Over a median (interquartile range) follow-up of 4.9 (4.1-5.7) years, the number (%) of primary outcome and all-cause mortality events in those who used aspirin (vs. those who did not), was 196 (6.5) versus 229 (6.9) and 146 (4.8) versus 147 (4.5), respectively. The adjusted hazard ratios (95% confidence interval) associated with aspirin use for the primary outcome and all-cause mortality were 0.94 (0.77-1.14) and 1.08 (0.85-1.36), respectively. In high-risk individuals with type 2 diabetes, the use of aspirin for primary prevention was not associated with a decreased risk of incident CVD or all-cause mortality.

Estimated impact of guidelines-based initiation of dual antihypertensive therapy on long-term cardiovascular outcomes in 1.1 million individuals.

Guidelines recommend initiation of dual combination antihypertensive therapy, preferably single-pill combination (SPC), in most patients with hypertension. Evidence on narrowing gaps in clinical practice relative to guidelines is limited. Monte Carlo simulation was applied to 1.1 million patients qualifying for dual combination therapy from a previously conducted retrospective analysis of clinical practice, hospital statistics, and national statistics in the UK. We provide 10-year Kaplan-Meier event rates for the primary endpoint representing a composite of nonfatal myocardial infarction, nonfatal stroke (ischemic or hemorrhagic), nonfatal heart failure hospitalization or cardiovascular death. Cox model results from a previously conducted study were utilized to estimate baseline risk, together with evidence on risk reduction from the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC) meta-analysis and published evidence on BP-lowering efficacy of antihypertensive therapies. In the overall population, estimated 10-year event rates for the primary endpoint in patients with 100% persistence in monotherapy were 17.0% for irbesartan (I) and 17.6% for ramipril (R). These rates were only modestly better than that observed in clinical practice (17.8%). In patients with 100% persistence in dual therapy, estimated event rates were 13.6% for combinations of Irbesartan+Amlodipine (ARR=8.7% compared to untreated) and 14.3% for Ramipril+Amlodipine (ARR=8.0% compared to untreated). The absolute risk of the primary endpoint was reduced by 15.9% in patients with ASCVD and 6.6% in those without ASCVD. Similarly, the absolute risk was reduced by 11.7% in diabetics and 7.8% in those without diabetes. This study represents the first to investigate guidelines-based treatment in hypertensive patients and demonstrates the opportunity for considerable risk reduction by ensuring recommended dual therapy in clinical practice, particularly in the form of SPC with high persistence, relative to no treatment or monotherapy.

Myocardial Bridging Increases the Risk of Adverse Cardiovascular Events in Patients without Coronary Atherosclerosis.

Background: Myocardial bridging (MB) is a congenital coronary anomaly and an important cause of chest pain. The long-term effects of MB on cardiovascular events remain elusive. Methods: We used the National Health Insurance Research Database of Taiwan to conduct an analysis. All patients who had undergone coronary angiography were considered for inclusion. The primary endpoint was a composite of nonfatal myocardial infarction, nonfatal ischemic stroke, and cardiovascular death. Results: We identified 10,749 patients from 2008 to 2018 and matched them with an equal number of controls by propensity-score matching. The mean follow-up period was 5.78 years. In patients without coronary artery disease, MB increased the risk of the composite endpoint (hazard ratio [HR]: 1.57, 95% confidence interval [CI]: 1.44-1.72, p < 0.001), which was driven by increased risks of nonfatal myocardial infarction and cardiovascular death. In patients with significant coronary artery disease, MB did not increase the risk of major adverse cardiovascular events. MB was identical to insignificant coronary artery disease from the viewpoint of clinical outcomes. Conclusions: The presence of MB significantly increases cardiovascular risks in patients with normal coronary vessels. Atherosclerotic coronary artery disease mitigates the effect of MB on cardiovascular outcomes. MB can be considered an insignificant coronary artery disease equivalent.

Glucagon-like-peptide-1 receptor agonists versus dipeptidyl peptidase-4 inhibitors and cardiovascular outcomes in diabetes in relation to achieved glycemic control. A Danish nationwide study.

To compare the cardiovascular preventive effect associated with glucagon-like-peptide-1 receptor agonists (GLP-1 RA) versus dipeptidyl peptidase-4 inhibitors (DPP-4i) according to the achieved target level of glycated hemoglobin (HbA1c). We used retrospective Danish registries to include type 2 diabetes patients already in metformin treatment initiating GLP-1 RA or DPP-4i between 2007 and 2021. Patients were included 6 months after GLP-1 RA or DPP-4i initiation. The last available HbA1c measurement before inclusion was collected. The achieved HbA1c level was categorized according to a target level below or above 53 mmol/mol (7%). The primary outcome was a composite of nonfatal myocardial infarction, nonfatal stroke, and all-cause death. We used a multivariable Cox proportional hazard model to estimate the effect of HbA1c levels on the outcome among GLP-1 RA users compared to DPP-4i users. The study included 13 634 GLP-1 RA users (median age 56.9, interquartile range [IQR]: 48.5-65.5; 53% males) and 39 839 DPP-4i users (median age 63.4, IQR: 54.6-71.8; 61% males). The number of GLP-1 RA and DPP-4i users according to achieved HbA1c levels were as follows: HbA1c ≤ 53 mmol/mol (≤7.0%): 3026 (22%) versus 4824 (12%); HbA1c > 53 mmol/mol (>7.0%): 6577 (48%) versus 17 508 (44%); missing HbA1c: 4031 (30%) versus 17 507 (44%). During a median follow-up of 5 years (IQR: 2.6-5.0), 954 GLP-1 RA users experienced the primary outcome compared to 7093 DPP-4i users. The 5-year risk (95% confidence interval [CI]) of the outcome associated with GLP1-RA versus DPP-4i according to HbA1c categories was as follows: HbA1c ≤ 53 mmol/mol: 10.3% (8.2-12.3) versus 24.3% (22.7-25.8); HbA1c > 53 mmol/mol: 16.0% (14.3-17.6) versus 21.1% (20.3-21.9); missing HbA1c: 17.1% (15.7-18.5) versus 25.6% (24.9-26.3). The preventive effect associated with GLP-1 RA versus DPP-4i was significantly enhanced when achieving lower HbA1c levels: HbA1c ≤ 53 mmol/mol: 0.65 (0.52-0.80); HbA1c > 53 mmol/mol: 0.92 (0.83-1.03); missing HbA1c: 0.92 (0.84-1.02) (p value for interaction <.001). GLP-1 RA use was associated with a lower rate of major adverse cardiovascular outcomes. The association was stronger in patients achieving the target glycemic level and weaker in patients not achieving the target glycemic level, suggestive of an interaction between achieved HbA1c level and GLP-1 RA.

DANSPOT: A Multicenter Stepped-Wedge Cluster-Randomized Trial of the Reclassification of Acute Myocardial Infarction: Rationale and Study Design.

Cardiac troponins are the preferred biomarkers for the diagnosis of acute myocardial infarction. Although sex-specific 99th percentile thresholds of troponins are recommended in international guidelines, the clinical effect of their use is poorly investigated. The DANSPOT Study (The Danish Study of Sex- and Population-Specific 99th percentile upper reference limits of Troponin) aims to evaluate the clinical effect of a prospective implementation of population- and sex-specific diagnostic thresholds of troponins into clinical practice. This study is a nationwide, multicenter, stepped-wedge cluster-randomized trial of the implementation of population- and sex-specific thresholds of troponins in 22 of 23 clinical centers in Denmark. We established sex-specific thresholds for 5 different troponin assays based on troponin levels in a healthy Danish reference population. Centers will sequentially cross over from current uniform manufacturer-derived thresholds to the new population- and sex-specific thresholds. The primary cohort is defined as patients with symptoms suggestive of acute coronary syndrome having at least 1 troponin measurement performed within 24 hours of arrival with a peak troponin value between the current uniform threshold and the new sex-specific female and male thresholds. The study will compare the occurrence of the primary outcome, defined as a composite of nonfatal myocardial infarction, unplanned revascularization, and all-cause mortality within 1 year, separately for men and women before and after the implementation of the new sex-specific thresholds. The DANSPOT Study is expected to show the clinical effects on diagnostics, treatment, and clinical outcomes in patients with myocardial infarction of implementing sex-specific diagnostic thresholds for troponin based on a national Danish reference population. URL: https://www.clinicaltrials.gov; Unique identifier: NCT05336435.

Heart failure: the grim reaper of the cardio-renal-metabolic triad.

Current understanding of the prognosis for patients with chronic kidney disease (CKD) and overlapping cardio-renal-metabolic components, specifically heart failure (HF) and diabetes mellitus (DM), remains limited. While previous studies have explored the interactions between CKD, HF, and DM, they have predominantly focused on cohorts of HF or DM patients. This study aims to fill this gap by investigating the long-term outcomes and treatment patterns in a cohort of CKD patients, particularly those with coexisting HF and DM. We analysed data from the Swedish national CKD patient cohort, the Swedish Renal Registry, with a follow-up period extending up to 10years. The study examined the risks of all-cause mortality, major adverse cardiovascular events (MACE)-defined as a composite of non-fatal myocardial infarction, hospitalization for congestive HF, non-fatal stroke, or cardiovascular death-and the initiation of kidney replacement therapy (KRT). Analyses were conducted using Cox proportional hazards and competing risk models. Among the 27647 patients, 48% had CKD alone, 12% had CKD with HF, 27% had CKD with DM, and 13% had CKD with both HF and DM. After 5years, mortality rates were 23% for patients with CKD, 30% for those with CKD/DM, 54% for CKD/HF, and 55% for CKD/HF/DM. The 10year absolute risk of MACE was 28% for CKD alone, 35% for CKD/DM, 67% for CKD/HF, and 73% for CKD/HF/DM. The adjusted hazard ratio (HR) for mortality was approximately three times higher in patients with any HF combination, with HRs of 2.57 [95% confidence interval (CI) 2.43-2.71] for CKD/HF and 3.22 (95% CI 3.05-3.39) for CKD/HF/DM, compared with CKD alone. The impact of HF on MACE prognosis was even more pronounced, with adjusted sub-hazard ratios (SHRs) of 3.33 (95% CI 3.14-3.53) for CKD/HF and 4.26 (95% CI 4.04-4.50) for CKD/HF/DM. Additionally, CKD patients diagnosed with HF were less likely to commence KRT, and the risk of death prior to KRT initiation was roughly twice as high for these groups, with SHRs of 2.05 (95% CI 1.93-2.18) for CKD+HF and 2.43 (95% CI 2.29-2.58) for CKD+HF+DM. In a cohort of CKD patients, having HF contributes substantially to increased mortality and the risk of MACE, and these patients are less likely to start KRT. These findings highlight the urgent need for targeted therapeutic strategies and management plans for CKD patients, particularly those with concurrent HF, to enhance patient prognosis.

Unstable Angina Risk Stratification Using High-Sensitivity Cardiac Troponin and Coronary Angiography

Patients formerly diagnosed with unstable angina (UA) are being reclassified as non-ST-elevation myocardial infarction (NSTEMI) with the widespread adoption of sensitive troponin assays (hsTn), leading to significant changes in the incidence and prognosis of UA. The main purpose of this study was to evaluate the value of hsTn and the presence of significant obstructive CAD in the risk stratification of patients with unstable angina. We conducted a retrospective, single-centre study of 742 patients hospitalized for UA between 2016-2021. The primary endpoint of this study was all-cause mortality. The secondary outcome (MACE) was defined as a composite of nonfatal myocardial infarction (MI), hospitalization for heart failure (hHF), and repeated coronary angiography due to recurring UA (rUA) after the index event. Outcomes were assessed within one month, one year, and up to 5 years of follow-up. The average follow-up duration was 45±24 months, and 37.2% (N=276) of patients completed a 5-year follow-up. No in-hospital death was observed, and 6.9% of patients died during follow-up, which was more commonly a late event (>12 months). The composite secondary endpoint (MI+hHF+rUA) was observed in 16.7% of the patients. There was 3.2% nonfatal MI, 2.3% hHF, and 11.6% rUA during follow-up. We developed a risk model (UA Mortality Risk) using variables with the highest discriminatory power: age, hsTn, and ST-segment deviation. Our model performed well against the GRACE and TIMI risk scores in predicting death during follow-up. Obstructive CAD on coronary angiography was the only independent predictor of MACE during follow-up. In conclusion, a contemporary cohort of patients with UA presented with favourable prognosis, particularly within the first year after the index event. Non-significant increases in HsTn levels add to the risk stratification of UA patients, and the presence of obstructive CAD was the only independent predictor of MACE, highlighting the potential importance of assessing coronary anatomy.

Prognostic impact of hypertension grading

BackgroundMost Hypertension Guidelines grade hypertension according to various cut-off values. We sought to investigate the prognostic impact of Grades 1 (140–159 and/or 90–99 mmHg), 2 (160–179 and/or 100–109 mmHg) and 3 (≥180 and/or ≥110 mmHg). MethodsWe followed for an average of 10 years a cohort of 3,150 initially untreated hypertensive patients (mean age 50 years, 44 % women) with no previous cardiovascular disease at entry. All patients underwent diagnostic tests including 24-hour ambulatory blood pressure (BP) monitoring. ResultsAt entry, average clinic BP was 156/97 mmHg and average 24-hour BP was 137/87 mmHg. During follow-up, 314 patients experienced a first major cardiovascular event (composite of non-fatal myocardial infarction or stroke, cardiovascular death, or hospitalization for heart failure). Event rate was not formally dissimilar between Grade 1 and Grade 2 (0.73 vs 0.95 per 100 patient-years, respectively; p = 0.06). It was higher in Grade 3 (1.93 per 100 patient-years; p < 0.01 vs Grade 1 and Grade 2). After adjustment for a robust set of covariables, the hazard ratio was not dissimilar between Grade 1 and Grade 2 (p = 0.27), and higher in Grade 3 than in Grade 1 (p < 0.01), but the excess risk in Grade 3 was no longer significant (hazard ratio: 1.25, 95 % CI 0.87–1.78; p = 0.22) after adjustment for 24-hour ambulatory systolic BP. ConclusionsWe were unable to find a significant difference in the relative hazard of cardiovascular events tied to hypertension Grades 1 and 2. Conversely, Grade 3 (clinic BP ≥180/110 mmHg) portends a higher cardiovascular risk, which is associated with higher levels of 24-hour ambulatory BP.

Systolic and diastolic blood pressure time in target range and cardiovascular outcomes in patients with hypertension and pre-frailty or frailty status.

In patients with hypertension and pre-frailty or frailty, the influence of systolic (SBP) and diastolic blood pressure (DBP) time in target range (TTR) on clinical outcomes is unclear. Thus, we conducted a post hoc analysis of the Systolic Blood Pressure Intervention Trial (SPRINT). Classifying 4208 participants into frail and non-frail groups using a frailty index, the study calculated blood pressure time in target range (BP-TTR) for the first three months using the Rosendaal method. The primary endpoint included a composite of nonfatal myocardial infarction (MI), acute coronary syndromes, stroke, acute decompensated heart failure (ADHF), and cardiovascular death. Relationships between BP-TTR and outcomes were analyzed using Kaplan-Meier curves, Cox models, and restricted cubic spline curves, with subgroup analysis for further insights. In a median follow-up of 3.17 years, primary outcomes occurred in 6.7% of participants. Kaplan-Meier analysis showed that a lower systolic blood pressure time in target range (SBP-TTR) (0%-25%) correlated with an increased cumulative incidence of the primary outcome (p<.001), nonfatal MI (P=.021), stroke (P=.004), and cardiovascular death (P=.002). A higher SBP-TTR (75%-<100%) was linked to a reduced risk of these outcomes. The restricted cubic spline (RCS) curve revealed a linear association between SBP-TTR and the primary outcome (non-linear P=.704). Similar patterns were observed for diastolic blood pressure time in target range (DBP-TTR). Subgroup analysis showed that the protective effect of higher SBP-TTR was less pronounced at low DBP-TTR levels (P for interaction=.023). In conclusion, this study highlights the importance of maintaining BP within the target range to mitigate cardiovascular risks in this population.

Reduced Alcohol Consumption and Major Adverse Cardiovascular Events Among Individuals With Previously High Alcohol Consumption

Cardiovascular benefits of mild to moderate alcohol consumption need to be validated in the context of behavioral changes. The benefits of reduced alcohol consumption among people who drink heavily across different subtypes of cardiovascular disease (CVD) are unclear. To investigate the association between reduced alcohol consumption and risk of major adverse cardiovascular events (MACEs) in individuals who drink heavily across different CVD subtypes. This cohort study analyzed data from the Korean National Health Insurance Service-Health Screening database and self-reported questionnaires. The nationally representative cohort comprised Korean citizens aged 40 to 79 years who had national health insurance coverage on December 31, 2002, and were included in the 2002 to 2003 National Health Screening Program. People who drank heavily who underwent serial health examinations over 2 consecutive periods (first period: 2005-2008; second period: 2009-2012) were included and analyzed between February and May 2023. Heavy drinking was defined as more than 4 drinks (56 g) per day or more than 14 drinks (196 g) per week for males and more than 3 drinks (42 g) per day or more than 7 drinks (98 g) per week for females. Habitual change in heavy alcohol consumption during the second health examination period. People who drank heavily at baseline were categorized into 2 groups according to changes in alcohol consumption during the second health examination period as sustained heavy drinking or reduced drinking. The primary outcome was the occurrence of MACEs, a composite of nonfatal myocardial infarction or angina undergoing revascularization, any stroke accompanied by hospitalization, and all-cause death. Of the 21 011 participants with heavy alcohol consumption at baseline (18 963 males [90.3%]; mean [SD] age, 56.08 [6.16] years) included in the study, 14 220 (67.7%) sustained heavy drinking, whereas 6791 (32.2%) shifted to mild to moderate drinking. During the follow-up of 162 378 person-years, the sustained heavy drinking group experienced a significantly higher incidence of MACEs than the reduced drinking group (817 vs 675 per 100 000 person-years; log-rank P = .003). Reduced alcohol consumption was associated with a 23% lower risk of MACEs compared with sustained heavy drinking (propensity score matching hazard ratio [PSM HR], 0.77; 95% CI, 0.67-0.88). These benefits were mostly accounted for by a significant reduction in the incidence of angina (PSM HR, 0.70; 95% CI, 0.51-0.97) and ischemic stroke (PSM HR, 0.66; 95% CI, 0.51-0.86). The preventive attributes of reduced alcohol intake were consistently observed across various subgroups of participants. Results of this cohort study suggest that reducing alcohol consumption is associated with a decreased risk of future CVD, with the most pronounced benefits expected for angina and ischemic stroke.

Circulating osteoprotegerin levels and cardiovascular outcomes in patients with pre-dialysis chronic kidney disease: results from the KNOW-CKD study.

While the relationship between circulating osteoprotegerin (OPG) and cardiovascular events is well-established in the general population, its association with cardiovascular risks in chronic kidney disease (CKD) patients remains less robust. This study hypothesized that elevated circulating OPG levels might be associated with an increased risk of major adverse cardiac events (MACE) in CKD patients, a total of 2,109 patients with CKD stages 1 through pre-dialysis 5 from the KNOW-CKD cohort were categorized into quartiles based on serum OPG levels. The primary outcome of the study was 3-point MACE, defined as a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiac death. The median follow-up duration was 7.9years. The cumulative incidence of 3-point MACE significantly varied across serum OPG levels in Kaplan-Meier curve analysis (P < 0.001, log-rank test), with the highest incidence observed in the 4th quartile. Cox regression analysis indicated that, relative to the 1st quartile, the risk of 3-point MACE was significantly higher in the 3rd (adjusted hazard ratio 2.901, 95% confidence interval 1.009 to 8.341) and the 4th quartiles (adjusted hazard ratio 4.347, 95% confidence interval 1.410 to 13.395). In conclusion, elevated circulating OPG levels are associated with adverse cardiovascular outcomes in pre-dialysis CKD patients.

Effects of finerenone and glucagon-like peptide 1 receptor agonists on cardiovascular and renal outcomes in type 2 diabetes mellitus: a systematic review and meta-analysis

ObjectiveTo assess the effects of finerenone and glucagon-like peptide 1 receptor agonists (GLP1-RA) on cardiovascular and renal outcomes in patients with type 2 diabetes mellitus (T2DM), and the relative cardiovascular benefits in patients with or without established atherosclerotic cardiovascular disease for different outcomes with these classes of drugs.MethodsWe searched PubMed, the Cochrane Library, and Embase from January 1, 2000, to December 30, 2022, to identify randomized controlled trials. The primary outcomes were the composite of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death (MACE); hospitalization for heart failure (HHF); and a composite of renal outcomes. The results were reported as hazard ratios (HRs) with 95% confidence intervals (CIs).ResultsIn total, we identified 11 trials and 73,927 participants, 13,847 (18.7%) in finerenone trials and 60,080 (81.3%) in GLP1-RA trials. Finerenone reduced the risk of MACE by 13% (HR, 0.87; 95% CI, 0.79–0.95; P = 0.003), while GLP1-RA reduced the risk in a similar magnitude by 13% (HR, 0.87; 95% CI, 0.83–0.92; P < 0.001). For both drug classes, the effect on lowering the risk of MACE was restricted to approximately 14% in patients with established atherosclerotic cardiovascular disease (HR, 0.86; 95% CI, 0.82–0.90; P < 0.001), whereas no effect was observed in patients without established atherosclerotic cardiovascular disease (HR, 0.93; 95% CI, 0.85–1.02; P = 0.12). GLP1-RA reduced myocardial infarction, stroke and cardiovascular death more than finerenone (which appeared to have no effect). Only finerenone was beneficial for reducing the risk of HHF (HR, 0.78; 95% CI, 0.66–0.92; P = 0.003). Both finerenone (HR, 0.84; 95% CI, 0.77–0.92; P < 0.001) and GLP1-RA (HR, 0.81; 95% CI, 0.76–0.86; P < 0.001) reduced the risk of kidney disease progression, including macroalbuminuria, and finerenone was superior to GLP1-RA in delaying deterioration of kidney function.ConclusionsFinerenone and GLP1-RA lead to a risk reduction in MACE to a similar degree in patients with established atherosclerotic cardiovascular disease. For both drug classes, the effect on lowering the risk of progression of kidney disease was also in a similar magnitude in patients with T2DM, whereas only finerenone had a significant protective effect against HHF. Treatment decisions for patients with T2DM should consider the clinical benefit profiles of each drug.

Kidney function and future risk of atherosclerotic cardiovascular disease: a study from, approximately half million adults

Abstract Background Data are lacking regarding contribution of kidney function towards atherosclerotic cardiovascular diseases (ASCVD) in young to middle aged adults. Purpose To evaluate the impact of kidney function on future risk of ASCVD in a large, young contemporary population without prior ASCVD. Methods This observational cohort study included young to middle aged adults (ages 30-55 years) without established ASCVD (as of January 1, 2006) who were members of an integrated healthcare delivery system in Northern California. Adjusted multivariate models (age, sex, race, diabetes, hypertension, HDL-C, LDL-C, total cholesterol, smoking, albuminuria) were specified to estimate risk ratios (RRs) for incident ASCVD events by kidney function (eGFR mL/min/1.732). Incident ASCVD events were defined as a composite of nonfatal myocardial infarction, ischemic stroke, or coronary heart disease death through December 31, 2020. Results A total of 426,735 individuals met the selection criteria. Mean age was 45.4 (±7.0) years. Fifty-five percent were women, and the median follow-up was 12.7 (IQR=11) years. In fully adjusted models, risk of future ASCVD, compared to patients with eGFR ≥ 60 was 1.7 (95% CI 1.5-1.9) for eGFR 30-59 RR and RR of 2.2 (95% CI 1.8- 2.7) for eGFR &amp;lt; 30. The kidney function-ASCVD associations were similar by sex for eGFR 30-59, but risks were accentuated among women with eGFR&amp;lt;30 (figure). Conclusions There was increased risk of future ASCVD with worsening kidney function. This risk was more pronounced among women. Using eGFR as part of risk assessment can inform targeting early interventions to prevent both kidney disease and subsequent ASCVD, especially in the era where effective pharmacotherapy such as SGLT2-Inhibitors have demonstrated renal and cardioprotective effects in high-risk populations.

The effects of canagliflozin in type 2 diabetes in subgroups defined by population-specific body mass index: Insights from the CANVAS Program and CREDENCE trial.

To assess the effects of canagliflozin on clinical outcomes and intermediate markers across population-specific body mass index (BMI) categories in the CANVAS Program and CREDENCE trial. Individual participant data were pooled and analysed in subgroups according to population-specific BMI. The main outcomes of interest were: major adverse cardiovascular events (MACE, a composite of nonfatal myocardial infarction, nonfatal stroke or cardiovascular death); composite renal outcome; and changes in systolic blood pressure (SBP), body weight, albuminuria and estimated glomerular filtration rate (eGFR) slope. Cox proportional hazards models and mixed-effect models were used. A total of 14 520 participants were included, of whom 9378 (65%) had obesity. Overall, canagliflozin reduced the risk of MACE (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.75 to 0.93) with no heterogeneity of treatment effect across BMI subgroups (Pheterogeneity = 0.76). Similarly, canagliflozin reduced composite renal outcomes (HR 0.75, 95% CI 0.66 to 0.84) with no heterogeneity across subgroups observed (Pheterogeneity = 0.72). The effects of canagliflozin on body weight and SBP differed across BMI subgroups (Pheterogeneity <0.01 and 0.04, respectively) but were consistent for albuminuria (Pheterogeneity = 0.60). Chronic eGFR slope with canagliflozin treatment was consistent across subgroups (Pheterogeneity >0.95). The cardiovascular and renal benefits of canagliflozin and its safety profile were consistent across population-specific BMI subgroups for adults in the CANVAS Program and CREDENCE trial.

AI-Guided Quantitative Plaque Staging Predicts Long-Term Cardiovascular Outcomes in Patients at Risk for Atherosclerotic CVD

BackgroundThe recent development of artificial intelligence–guided quantitative coronary computed tomography angiography analysis (AI-QCT) has enabled rapid analysis of atherosclerotic plaque burden and characteristics. ObjectivesThis study set out to investigate the 10-year prognostic value of atherosclerotic burden derived from AI-QCT and to compare the spectrum of plaque to manually assessed coronary computed tomography angiography (CCTA), coronary artery calcium scoring (CACS), and clinical risk characteristics. MethodsThis was a long-term follow-up study of 536 patients referred for suspected coronary artery disease. CCTA scans were analyzed with AI-QCT and plaque burden was classified with a plaque staging system (stage 0: 0% percentage atheroma volume [PAV]; stage 1: >0%-5% PAV; stage 2: >5%-15% PAV; stage 3: >15% PAV). The primary major adverse cardiac event (MACE) outcome was a composite of nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, and all-cause mortality. ResultsThe mean age at baseline was 58.6 years and 297 patients (55%) were male. During a median follow-up of 10.3 years (IQR: 8.6-11.5 years), 114 patients (21%) experienced the primary outcome. Compared to stages 0 and 1, patients with stage 3 PAV and percentage of noncalcified plaque volume of >7.5% had a more than 3-fold (adjusted HR: 3.57; 95% CI 2.12-6.00; P < 0.001) and 4-fold (adjusted HR: 4.37; 95% CI: 2.51-7.62; P < 0.001) increased risk of MACE, respectively. Addition of AI-QCT improved a model with clinical risk factors and CACS at different time points during follow-up (10-year AUC: 0.82 [95% CI: 0.78-0.87] vs 0.73 [95% CI: 0.68-0.79]; P < 0.001; net reclassification improvement: 0.21 [95% CI: 0.09-0.38]). Furthermore, AI-QCT achieved an improved area under the curve compared to Coronary Artery Disease Reporting and Data System 2.0 (10-year AUC: 0.78; 95% CI: 0.73-0.83; P = 0.023) and manual QCT (10-year AUC: 0.78; 95% CI: 0.73-0.83; P = 0.040), although net reclassification improvement was modest (0.09 [95% CI: −0.02 to 0.29] and 0.04 [95% CI: −0.05 to 0.27], respectively). ConclusionsThrough 10-year follow-up, AI-QCT plaque staging showed important prognostic value for MACE and showed additional discriminatory value over clinical risk factors, CACS, and manual guideline-recommended CCTA assessment.

#3785 PROPOSAL OF A NOVEL RISK PREDICTION SCORE FOR MAJOR ADVERSE CARDIOVASCULAR EVENTS IN LUPUS NEPHRITIS

Abstract Background and Aims Patients with systemic lupus erythematosus have an increased risk of cardiovascular diseases (CVD) vastly contributing to morbidity and mortality. Besides traditional risk factors, lupus-related factors also contribute to the overall risk. Our major objective was to identify both traditional and non-traditional factors that could aid the prediction of CVD risk and major adverse cardiovascular events (MACE) in this population. MACE was defined as the composite of nonfatal myocardial infarction, hospitalization due to heart failure, coronary revascularization, stroke, and cardiovascular death. We also aimed to create a model that could be applied after a prompt assessment of lupus nephritis patients to estimate the long-term CVD risk. Method We conducted a single-center retrospective analysis on lupus nephritis patients. Demographic variables, cardiovascular events, clinical and histological data were collected from patients who underwent kidney biopsy between 2005 and 2020 (Figure 1). Chi-square, Mann-Whitney U-test, and logistic regression analyses were performed to investigate risk factors for MACE (IBM SPSS Statistics v28). Receiver Operating Characteristic (ROC) curve was used to determine optimal cut-off values. The study was approved by the Semmelweis University Regional and Institutional Committee of Science and Research Ethics (SE RKEB 225/2018). Results 91 patients were enrolled in this period. The mean age was 37.3±12.3 years, 86% females, and the mean follow-up time was 62±48 months. Fourteen patients (15.4%) suffered at least one MACE, of which 13 (14.3%) occurred after diagnosing lupus and 8 (8.8%) after the biopsy. Two patients deceased of a cardiovascular event. Out of the traditional risk factors, increased age (35.8±11.1 vs 45.5±15.1 years, p = 0.012) entailed a higher occurrence of MACE. Complete white blood cell (3.54±0.41 vs 3.25±0.87 Giga/liter, p = 0.026) and neutrophil count (2.85±0.33 vs 3.11±0.83 Giga/liter, p = 0.001) were higher, while diastolic blood pressure was lower (89.5±10.96 vs 78.43±6.9 mmHg, p&amp;lt;0.001) at the time of the biopsy in patients with MACE complication. Age, neutrophil count, and diastolic blood pressure were proven to be independent predictors of MACE (Table 1). Based on these observations, we proposed a new model (CANDE: Cardiovascular risk –based on Age, Neutrophil count, and Diastolic blood pressure– Estimation score) that is a stronger predictor of MACE and can be used to calculate MACE risk from the time of the biopsy in lupus nephritis patients (Figure 1). The higher the score was, the more often the MACE cases were present (Table 1). ROC curve analysis demonstrated that at 0.78 cut-off value the score predicts MACE occurrence at the time of the biopsy with a sensitivity of 0.75 and a specificity of 0.61. The analyses of MACE subgroups revealed that neutrophil-lymphocyte ratio was elevated in patients who were hospitalized because of heart failure (5.66±4.61 vs 9.68±6.46, p = 0.046), while neutrophil-thrombocyte ratio was higher in patients with coronary revascularization in their medical history (0.023±0.015 vs 0.06±0.028, p = 0.02). This also indicates the importance of neutrophils in CVD risk assessment. Conclusion Age, neutrophil count, and diastolic blood pressure are demonstrated to be independent risk factors of MACE in lupus nephritis. The score calculated from these parameters (CANDE) is a stronger predictor of MACE at the time of the biopsy. A larger cohort is needed to validate these promising results.

IMPACT OF RAMIPRIL/AMLODIPINE DOSE COMBINATIONS OF SINGLE-PILL VERSUS FREE EQUIVALENT COMBINATIONS ON PERSISTENCE AND MAJOR ADVERSE CARDIOVASCULAR EVENTS: A REAL-WORLD ANALYSIS

Objective: Guidelines recommend use of single-pill combination (SPC) for management of hypertensive patients. Very few studies compared SPCs and free equivalent combinations (FEC) focusing on short-term persistence and major adverse cardiovascular events (MACE) outcomes. This study assessed the impact of different dose combinations of ramipril/amlodipine (R/A) SPC versus FEC on treatment persistence and MACE in patients with hypertension over a 5-year period. Design and method: This real-world, retrospective, observational cohort study was performed using National Health Insurance Fund of Hungary database. The study included hypertensive patients aged &gt; = 18 years who initiated on R/A SPC or FEC, of different dose combinations: R/A 5/5 mg, 5/10 mg, 10/5 mg and 10/10 mg, between 01 April 2012 and 31 December 2018. Primary endpoint was the long-term persistence rate, applying 90-days grace period, between R/A SPC and FEC. Secondary endpoint was the rate of MACE (composite of non-fatal myocardial infarction, stroke, hospitalization for heart failure and all-cause death). Analyses were performed using Cox-proportional hazard model and propensity score sub-classification method to adjust the imbalances in baseline characteristics. Results: Overall, 173,206 patients with hypertension were included (SPC group, N = 104,882 [61%], and FEC group, N = 68,324 [39%]); R/A 5/5 mg representing the largest proportion (N = 107,992 [62%]). In SPC and FEC groups, mean (SD) age was 61.31 (13.75) and 66.08 (13.10) years and proportion of male was 45.4% and 43.1%, respectively. As shown in Table 1, the rate of non-persistence was significantly lower with all R/A SPCs compared to FECs from Month 1 to Month 24 (P &lt; 0.001). Thereafter, the rate of non-persistence remained significantly lower in the SPC groups except in the R/A 5/5 mg dose. MACE was significantly reduced with all R/A SPCs compared to FECs (HR 0.68–0.73; P &lt; = 0.002). There was no impact of age and gender on the association between the treatment and persistence rate or MACE outcomes. Conclusions: Our results confirm the beneficial effects of SPCs compared to FECs in achieving long-term improvement on persistence rate and MACE outcomes in patients with hypertension and support current guidelines recommending a widespread use of SPCs.

Risk of atherosclerotic cardiovascular disease in patients with premature ASCVD: A study from approximately 1 million young adults

Abstract Funding Acknowledgements Type of funding sources: None. Background Risk of atherosclerotic cardiovascular disease (ASCVD) attributable to premature ASCVD remains poorly understood. Purpose To evaluate the risk of ASCVD among those with premature ASCVD versus those without in a large contemporary population. Methods This observational cohort study included young adults (ages 30-55 years) with and without prior ASCVD (as of January 1, 2006) who were members of an integrated healthcare delivery system in Northern California. Adjusted multivariate models were specified to estimate risk ratios (RRs) for incident ASCVD events by ASCVD status at baseline. Incident ASCVD events were defined as a composite of nonfatal myocardial infarction, ischemic stroke, or coronary heart disease death through December 31, 2020. Results A total of 929,214 individuals met the selection criteria of no prior ASCVD and 5,703 with prior ASCVD. Mean age was 43.9 (±7.3) years and 50.0 (±5.2) years, respectively. Fifty-two and thirty percent were women in each cohort, and the median follow-up was 11.8 and 8.3 years, respectively. Crude ASCVD rate was 2.1 and 24.5 events per 1,000 person-years, respectively. Age-adjusted Kaplan-Meier curves for ASCVD in individuals with and without prior ASCVD in Figure. In models adjusted for demographics (sex, age, race) and traditional risk factors (diabetes, hypertension, LDL-cholesterol, HDL-cholesterol, total cholesterol, smoking), individuals with prior ASCVD had RR of 4.6 (95% CI 4.3-5.0) for CHD, RR of 3.0 (95% CI 2.7-3.4) for stroke and RR of 4.1 (95% CI 3.8-4.3) for ASCVD. Conclusions Risk of ASCVD among those with prior ASCVD was several-fold greater compared to those without prior ASCVD. Continued efforts for secondary prevention are needed in this vulnerable high-risk population.

Colchicine Use and Major Adverse Cardiovascular Events in Male Patients with Gout and Established Coronary Artery Disease: A Veterans Affairs Nested Retrospective Cohort Study

Background: Despite colchicine’s proven efficacy in the non-gout population, the effects of colchicine on the risk of major adverse cardiovascular events (MACE) among high-risk patients with gout remain to be determined. The purpose of this study is to evaluate the association between colchicine use and MACE in gout patients with preexisting coronary artery disease (CAD). Methods: This retrospective cohort study followed patients with gout and established CAD within the VA New York Harbor Healthcare System who did or did not use colchicine regularly (&gt;30 continuous days prescription with at least 1 refill). The primary outcome was first MACE, defined as a composite of non-fatal myocardial infarction, coronary artery bypass graft, non-fatal stroke, and all-cause mortality. Part I of the primary analysis compared MACE between colchicine users and nonusers. Part II of the study compared MACE within the colchicine-use group, divided into quartiles based on consistency of colchicine use (i.e., percentage of time on colchicine). Results: Among 1638 patients with gout, 355 had established CAD (239 colchicine users and 116 nonusers). In this cohort, the odds of MACE were similar between any colchicine use compared to nonuse (OR 1.14; 95% CI (0.59–2.20)); however, colchicine users overall had a higher baseline cardiovascular risk profile than nonusers, suggesting that colchicine may have served to equilibrate risk between the two groups. Moreover, patients in the highest continuous colchicine-use quartile (&gt;70% of observation period on colchicine) demonstrated lower odds of MACE compared to those in the lowest three quartiles (OR 0.35; 95% CI (0.13–0.93)), with no difference in baseline risk. Additionally, colchicine users had a numerically lower rate of MACE during periods of active use compared with periods of lapse. Kaplan–Meier analysis revealed a difference in cumulative MACE over time, favoring the subgroup with the most consistent colchicine use (plog-rank = 0.01). Conclusions: Despite higher CV risk, gout patients with CAD receiving colchicine had no higher rates of MACE than those not receiving colchicine. Among all patients with gout and CAD treated with colchicine, those with the most consistent colchicine use had lower odds of MACE, and event rates were lower during active use. Colchicine protection against cardiovascular events may require maintenance of colchicine bloodstream levels.