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Aims: Whether electrocardiographic (ECG) measurements predict mortality in chronic heart failure with reduced ejection fraction (HFrEF) is unknown. Methods and results: We studied 4880 patients from the Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA) trial with a baseline 12‐lead ECG. Associations between ECG measurements and mortality were estimated as hazard ratios (HR) and adjusted for the Meta‐Analysis Global Group in Chronic Heart Failure (MAGGIC) risk score, N‐terminal pro‐B‐type natriuretic peptide, and index event. Select interactions between ECG measurements, patient characteristics and mortality were examined. Over a median of 10.8 months, there were 824 cardiovascular (CV) deaths (214 sudden) and 1005 all‐cause deaths. Median age was 68 years (interquartile range [IQR] 60–76), 24% were women, median ejection fraction was 30% (IQR 23–35), 41% had New York Heart Association class III/IV, and median MAGGIC score was 24 (IQR 19–28). After multivariable adjustment, significant associations existed between heart rate (per 5 bpm: HR 1.02), QRS duration (per 10 ms: HR 1.02), absence of left ventricular hypertrophy (HR 0.64) and CV death, and similarly so with all‐cause death (HR 1.02; HR 1.02; HR 0.61, respectively). Contiguous pathologic Q waves were significantly associated with sudden death (HR 1.46), and right ventricular hypertrophy with all‐cause death (HR 1.44). The only sex‐based interaction observed was for pathologic Q waves on CV (men: HR 1.05; women: HR 1.64, pinteraction = 0.024) and all‐cause death (men: HR 0.99; women: HR 1.57; pinteraction = 0.010). Whereas sudden death doubled in females, it did not differ among males (male: HR 1.25, 95% confidence interval [CI] 0.87–1.79; female: HR 2.50, 95% CI 1.23–5.06; pinteraction = 0.141). Conclusion: Routine ECG measurements provide additional prognostication of mortality in high‐risk HFrEF patients, particularly in women with contiguous pathologic Q waves. [ABSTRACT FROM AUTHOR]

Aim: Vericiguat significantly reduced the primary composite outcome of heart failure (HF) hospitalization or cardiovascular death in the VICTORIA trial. It is unknown if these outcome benefits are related to reverse left ventricular (LV) remodelling with vericiguat in patients with HF with reduced ejection fraction (HFrEF). The aim of this study was to compare the effects of vericiguat versus placebo on LV structure and function after 8 months of therapy in patients with HFrEF. Methods and results: Standardized transthoracic echocardiography (TTE) was performed at baseline and after 8 months of therapy in a subset of HFrEF patients in VICTORIA. The co‐primary endpoints were changes in LV end‐systolic volume index (LVESVI) and LV ejection fraction (LVEF). Quality assurance and central reading were performed by an echocardiographic core laboratory blinded to treatment assignment. A total of 419 patients (208 vericiguat, 211 placebo) with high‐quality paired TTE at baseline and 8 months were included. Baseline clinical characteristics were well balanced between treatment groups and echocardiographic characteristics were representative of patients with HFrEF. LVESVI significantly declined (60.7 ± 26.8 to 56.8 ± 30.4 ml/m2; p < 0.01) and LVEF significantly increased (33.0 ± 9.4% to 36.1 ± 10.2%; p < 0.01) in the vericiguat group, but similarly in the placebo group (absolute changes for vericiguat vs. placebo: LVESVI −3.8 ± 15.4 vs. −7.1 ± 20.5 ml/m2; p = 0.07 and LVEF +3.2 ± 8.0% vs. +2.4 ± 7.6%; p = 0.31). The absolute rate per 100 patient‐years of the primary composite endpoint at 8 months tended to be lower in the vericiguat group (19.8) than the placebo group (29.6) (p = 0.07). Conclusions: In this pre‐specified echocardiographic study, significant improvements in LV structure and function occurred over 8 months in both vericiguat and placebo in a high‐risk HFrEF population with recent worsening HF. Further studies are warranted to define the mechanisms of vericiguat's benefit in HFrEF. [ABSTRACT FROM AUTHOR]

This study combined the kernel smoothing procedure and a nonparametric differential item functioning statistic--Cochran's Z--to statistically test the difference between the kernel-smoothed item response functions for reference and focal groups. Simulation studies were conducted to investigate the Type I error and power of the proposed kernel-smoothed Cochran's Z. For the purpose of comparison, the Type I error and power rates with no correction and with regression correction were also include in the simulation. The results of this study suggest the Type I error and power performance of Cochran's Z improved when kernel smoothing was applied. (Contains 4 tables and 1 figure.)

The purpose of this study is to describe how the attribute hierarchy method (AHM) can be used to evaluate differential group performance at the cognitive attribute level. The AHM is a psychometric method for classifying examinees' test item responses into a set of attribute-mastery patterns associated with different components in a cognitive model of task performance. Attribute probabilities, computed using a neural network, can be estimated on each attribute for each examinee thereby providing specific information about the examinee's attribute-mastery level. These probabilities can also be compared across groups. We describe a four-step procedure for estimating and interpreting group differences using the AHM. We also provide an example using student response data from a sample of algebra items on the SAT to illustrate our pattern recognition approach for studying group differences.

Objectives: Remote ischaemic conditioning (RIC) has been tested as a possible strategy for mitigating reperfusion injury in ST elevation myocardial infarction (STEMI) with primary percutaneous coronary intervention (PPCI). However, surrogate outcomes have shown inconsistent effects with lack of clinical correlation.Methods: We performed a registry-based randomised study of patients with STEMI allocated to RIC (4 cycles of blood pressure cuff inflation to 200 mm Hg for 5 min of ischaemia followed by 5 min of reperfusion) or standard of care (SOC) during PPCI. We examined the associations of RIC on core laboratory measurements of myocardial perfusion, infarct size (IS), left ventricular (LV) performance and clinical outcomes.Results: A total of 252 patients were enrolled. The median age was 61 (IQR: 55-70) years and 72.8% were male. Sum ST segment deviation resolution ≥50% was similar between RIC and SOC (65.2% vs 55.7%, p=0.269). In those with 3-day cardiovascular MRI (n=88), no difference in median (25th, 75th percentiles) IS (14.9% (4.5%, 23.1%) vs 16.1% (3.3%, 22.0%), p=0.980), LV dimensions (LV end-diastolic volume index: 78.7 (71.1, 91.2) mL/m2 vs 79.9 (71.2, 88.8) mL/m2, p=0.630; LV end-systolic volume index: 48.8 (35.7, 51.4) mL/m2 vs 37.9 (31.8, 47.5) mL/m2, p=0.551) or ejection fraction (50.0% (41.0%-55.0%) vs 50.0% (43.0%-56.0%), p=0.554) was demonstrated. Similar results were observed with 90-day cardiovascular MRI. At 1 year, the clinical composite of death, congestive heart failure, cardiogenic shock and recurrent myocardial infarction was similar in RIC and SOC (21.7% vs 13.3%, p=0.110).Conclusions: In a contemporary registry-based randomised study of patients with STEMI undergoing PPCI, adjunctive therapy with RIC did not improve myocardial perfusion, reduce IS or alter LV performance. Consequently, there was no difference in clinical outcomes within 1 year.Trial Registration Number: NCT03930589. [ABSTRACT FROM AUTHOR]

Objective: Phenotypic heterogeneity among patients with type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD) is ill defined. We used cluster analysis machine-learning algorithms to identify phenotypes among trial participants with T2DM and ASCVD.Research Design and Methods: We used data from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) study (n = 14,671), a cardiovascular outcome safety trial comparing sitagliptin with placebo in patients with T2DM and ASCVD (median follow-up 3.0 years). Cluster analysis using 40 baseline variables was conducted, with associations between clusters and the primary composite outcome (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina) assessed by Cox proportional hazards models. We replicated the results using the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial.Results: Four distinct phenotypes were identified: cluster I included Caucasian men with a high prevalence of coronary artery disease; cluster II included Asian patients with a low BMI; cluster III included women with noncoronary ASCVD disease; and cluster IV included patients with heart failure and kidney dysfunction. The primary outcome occurred, respectively, in 11.6%, 8.6%, 10.3%, and 16.8% of patients in clusters I to IV. The crude difference in cardiovascular risk for the highest versus lowest risk cluster (cluster IV vs. II) was statistically significant (hazard ratio 2.74 [95% CI 2.29-3.29]). Similar phenotypes and outcomes were identified in EXSCEL.Conclusions: In patients with T2DM and ASCVD, cluster analysis identified four clinically distinct groups. Further cardiovascular phenotyping is warranted to inform patient care and optimize clinical trial designs. [ABSTRACT FROM AUTHOR]

Objectives: To describe and evaluate outcomes in STEMI patients sustained on clopidogrel compared to those switched to ticagrelor following fibrinolysis. Background: World‐wide, many STEMI patients cannot achieve timely PCI and therefore require fibrinolysis. Although comparable 30‐day and 1‐year safety was shown with clopidogrel or ticagrelor in the TREAT study, there is paucity of long‐term outcomes in pharmacoinvasive treated STEMI. Methods: We conducted an observational cohort study evaluating consecutive pharmacoinvasive STEMI patients treated in a network, comparing those switched to ticagrelor to those sustained on clopidogrel. The primary efficacy composite was one‐year all‐cause death, recurrent myocardial infarction, and stroke with major bleeding and intracranial hemorrhage (ICH) as the safety outcomes. Multivariable Cox regression model was used to examine the association between P2Y12 inhibitor and outcomes with inverse probability weighting. Results: Of 1426 pharmacoinvasive STEMI patients, 28% (n = 396) were converted to ticagrelor at a mean of 9.9 h after fibrinolysis with comparable GRACE Risk Scores (median; 158 vs 157, p0.352). The primary composite occurred in 3.5% of ticagrelor and 7.0% of clopidogrel treated patients (p0.014). Following adjustment, ticagrelor was associated with a 54% lower composite outcome (adjusted HR 0.46, 95% confidence interval 0.26–0.84). Major bleeding 6.3% vs 6.1% (NS) and ICH 0.0% vs 0.2% (NS) were similar. Conclusions: In a prospective STEMI cohort, switching to ticagrelor compared with sustaining clopidogrel following fibrinolysis pharmacoinvasive reperfusion reduced recurrent ischemic events at 1‐year with no differences in major bleeding or ICH. Aligned with randomized data, these findings provide support to switch pharmaco‐invasively treated STEMI patients. [ABSTRACT FROM AUTHOR]

Aims: Whether glycaemic control is associated with cardiovascular outcomes in patients with type 2 diabetes (T2D) is unclear. Consequently, we assessed the relationship between glycated haemoglobin (HbA1c) and cardiovascular outcomes in a placebo‐controlled randomized trial which demonstrated no cardiovascular effect of sitagliptin in patients with T2D and atherosclerotic vascular disease. Methods and results: Secondary analysis of 14 656 TECOS participants with time to event analyses using multivariable Cox proportional hazard models. During a median 3.0 (interquartile range 2.3–3.8) year follow‐up, 456 (3.1% of 14 656) patients had first hospitalization for heart failure (HF), 1084 (11.5%) died, 1406 (9.6%) died or were hospitalized for HF, and 1689 (11.5%) had a non‐HF cardiovascular event (cardiovascular death, non‐fatal stroke, non‐fatal myocardial infarction, or hospitalization for unstable angina). Associations between baseline or time‐varying HbA1c and cardiovascular outcomes were U‐shaped, with the lowest risk when HbA1c was around 7%. Each one‐unit increase in the time‐varying HbA1c above 7% was associated with an adjusted hazard ratio (HR) of 1.21 [95% confidence interval (CI) 1.11–1.33] for first HF hospitalization, 1.11 (1.03–1.21) for all‐cause death, 1.18 (1.09–1.26) for death or HF hospitalization, and 1.10 (1.02–1.17) for non‐HF cardiovascular events. Each one‐unit decrease in the time‐varying HbA1c below 7% was associated with an adjusted HR of 1.35 (95% CI 1.12–1.64) for first HF hospitalization, 1.37 (1.16–1.61) for death, 1.42 (1.23–1.64) for death or HF hospitalization, and 1.22 (1.06–1.41) for non‐HF cardiovascular events. Conclusion: Glycated haemogobin exhibits a U‐shaped association with cardiovascular outcomes in patients with T2D and atherosclerotic vascular disease, with nadir around 7%. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT00790205. [ABSTRACT FROM AUTHOR]

Background: Obesity is a risk factor for type 2 diabetes (T2D) and cardiovascular disease (CVD). Whether obesity affects outcomes among those with T2D and atherosclerotic CVD (ASCVD) remains uncertain. Our objective was to investigate the relationship between body mass index (BMI) and ASCVD outcomes among TECOS participants with T2D and ASCVD.Methods: BMI categories were defined as underweight/normal weight (BMI <25 kg/m2), overweight (25-29.9 kg/m2), obese class I (30-34.9 kg/m2), obese class II (35-39.9 kg/m2), and obese class III (≥ 40 kg/m2). Asian-specific BMI categories were applied to Asian participants. Kaplan-Meier survival analysis and Cox proportional hazards models were used to examine associations between baseline BMI and a composite CV outcome (CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina).Results: For 14,534 TECOS patients with available BMI, mean age was 65.5 years; 29.3% were female, 32.0% non-White, and 23.1% insulin-treated, with median 3 years' follow-up. At baseline, 11.6% (n = 1686) were underweight/normal weight, 38.1% (n = 5532) overweight, 32.2% (n = 4683) obese class I, 12.4% (n = 1806) obese class II, and 5.7% (n = 827) obese class III. The composite CV outcome occurred in 11.4% (n = 1663) of participants; the outcome risk was lower, compared with under/normal weight, in overweight (HR 0.83, 95% CI 0.71-0.98) and obese class I (HR 0.79, 95% CI 0.67-0.93) individuals. Obesity was not associated with worse glycemic control.Conclusions: The majority of TECOS participants with ASCVD and T2D were overweight or obese, yet overweight or obese class I individuals had lower CV risk than those who were under/normal weight. These results suggest the presence of an obesity paradox, but this paradox may reflect an epidemiological artifact rather than a true negative association between normal weight and clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: The effects of β-blocker therapy in patients with type 2 diabetes (T2D) and established atherosclerotic cardiovascular disease (ASCVD) are unclear. We sought to evaluate associations between β-blocker use in T2D with ASCVD and cardiovascular (CV) outcomes.Methods: In patients with T2D and ASCVD enrolled in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), an inverse probability of treatment-weighted Cox proportional hazards model was used to examine the association between baseline β-blocker therapy (at randomization) and the primary CV composite (defined as CV death, non-fatal myocardial infarction [MI], non-fatal stroke, or hospitalization for unstable angina), including in subgroups with prior MI and heart failure (HF); other outcomes evaluated included individual components of the primary composite, hospitalization for HF, and severe hypoglycemic events.Results: Of the 14,671 patients randomized, 9322 (64%) were on a β-blocker at baseline; these patients were more likely to have prior MI or HF. Over a median 3.0 (25th, 75th percentile: 2.2, 3.6) years, the risk of the primary CV composite was significantly higher with baseline β-blocker use versus no β-blocker use (4.5 vs. 3.4 events/100-patient years, adjusted hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.05-1.29); no significant interaction was noted for patients with versus without prior MI or HF. Baseline β-blocker use was not associated with risks for severe hypoglycemic events (HR 1.14, 95% CI 0.88-1.48).Conclusions: In this observational analysis of T2D and ASCVD, baseline β-blocker use was not associated with risks for severe hypoglycemia yet also was not associated with CV risk reduction over 3 years of follow-up, supporting a randomized examination of chronic β-blocker therapy in this patient population. (TECOS ClinicalTrials.gov number, NCT00790205). [ABSTRACT FROM AUTHOR]

Background Several accelerated diagnostic protocols ( ADPs) have been developed to allow emergency department ( ED) physicians to identify appropriate patients for safe early discharge after presentation with symptom of chest pain. Most ADPs require chest pain to be described and modify the algorithm based on the subjective chest pain characteristics. We investigated the performance of three established major ADPs simplified by eliminating the need for chest pain as a descriptor. Methods We pooled patients from PROACT-3 and -4 trials, in which patients presenting to emergency medical services with chest pain or dyspnea were enrolled. The simplified Vancouver Chest Pain Rule ( sVCPR), the simplified Emergency Department Assessment of Chest Pain Score ( sEDACS) ADP and the Accelerated Diagnostic protocol to Assess Patients with chest pain using contemporary troponins as the only biomarker ( ADAPT- ADP) were compared using the sensitivity, specificity, and positive and negative predictive values ( NPV). The primary outcome of interest was 30-day major adverse cardiac events ( MACE); the diagnosis of acute coronary syndrome ( ACS) occurring within 30 days after ED presentation was also explored. Results A total of 1,081 patients were included (median age = 67 years, 53% male, median GRACE score = 113) of which 222 ACS diagnoses and 150 cardiac events occurred within 30 days after index ED presentation. The sVCPR, sEDACS ≥ 3, and ADAPT- ADP, respectively, identified 9.7, 13.3, and 4.1% of patients as low risk with a sensitivity and NPV of 100% for the primary outcome of 30-day MACE. The sEDACS- ADP identified 24.2% of patients as low risk with a cut-point score of 4 (sensitivity of 98.0% and NPV of 98.8%). The sVCPR, sEDACS ≥ 3, and ADAPT- ADP, respectively, had NPVs of 98.1, 95.8, and 93.3% in identifying patients at higher risk of ACS diagnosis within 30 days after index ED visit. Conclusion The diagnostic protocols performed well without their chest pain characteristics component. Further studies are suggested to explore the performance of ADPs when these simplified ADPs are combined with high-sensitive troponin assays. [ABSTRACT FROM AUTHOR]

Coronary plaque rupture mediating acute ST segment elevation myocardial infarction (STEMI) is associated with a systemic inflammatory response. Whether early temporal changes in inflammatory biomarkers are associated with angiographic and electrocardiographic markers of reperfusion and subsequent clinical outcomes is unclear. In the APEX-AMI biomarker substudy, 376 patients with STEMI had inflammatory biomarkers measured at the time of hospital presentation and 24 h later. The primary outcome was the 90-day composite of death, shock, or heart failure. Secondary reperfusion outcomes were (1) worst least residual ST segment elevation (ST-E: <1 mm, 1 to <2 mm, ≥2 mm) and (2) post-percutaneous coronary intervention (PCI) TIMI flow grade (0/1/2 vs 3) and TIMI myocardial perfusion grade (TMPG 0/1 vs 2/3). The 90-day incidence of death, shock or heart failure was 21.3 % in this cohort. Electrocardiographic reperfusion (worst residual ST-E <1 mm, 1 to <2 mm, ≥2 mm) was associated with differences in 24 h change in N-terminal proB-type natriuretic peptide (NT-proBNP) (1192.8, 1332.5, 1859.0 ng/mL; p = 0.043) and the pro-inflammatory cytokines Interleukin (IL)-6 (14.0, 13.6, 22.1 pg/mL; p = 0.016), IL-12 (−0.5, −0.9, −0.1 pg/mL; p = 0.013), and tumor necrosis factor α (TNFα) (1.0, 0.6, 3.6 pg/mL; p = 0.023). Angiographic reperfusion (TMPG 0/1 vs 2/3) was associated with changes in median NT-proBNP (2649.3, 1382.7 ng/mL; p = 0.002) and IL-6 (28.7, 15.1; p = 0.040). After adjustment for baseline covariates, the 24 h change in the pro-inflammatory cytokine TNFα [hazard ratio (HR) 0.49; 95 % CI 0.26-0.95; p = 0.035] and the anti-inflammatory cytokine IL 10 (HR 1.41; 95 % CI 1.06-1.87; p = 0.018) were independently associated with the primary composite outcome. Successful coronary reperfusion was associated with less systemic inflammatory response and greater temporal inflammatory changes were independently associated with higher 90-day composite of death, shock, or heart failure. These findings provide support for an association between success of reperfusion, an acute STEMI inflammatory response and subsequent clinical outcomes. [ABSTRACT FROM AUTHOR]