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Background: In the VICTORIA trial (Vericiguat Global Study in Patients with Heart Failure with Reduced Ejection Fraction), anemia occurred more often in patients treated with vericiguat (7.6%) than with placebo (5.7%). We explored the association between vericiguat, randomization hemoglobin, development of anemia, and whether the benefit of vericiguat related to baseline hemoglobin. Methods: Anemia was defined as hemoglobin Results: At baseline, 1719 (35.7%) patients had World Health Organization anemia; median hemoglobin was 13.4 g/L (25th, 75th percentile: 12.1, 14.7 g/dL). At 16 weeks from randomization, 1643 patients had World Health Organization anemia (284 new for vericiguat and 219 for placebo), which occurred more often with vericiguat than placebo ( P Conclusions: Anemia was common at randomization and lower hemoglobin was associated with a greater frequency of clinical events. Although vericiguat modestly lowered hemoglobin by 16 weeks, this effect did not further progress nor was it related to the treatment benefit of vericiguat. Registration: URL: https://www.clinicaltrials.gov : Unique identifier: NCT02861534.

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.

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.

The effect of vericiguat on sequential N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and influence of this relationship on clinical outcomes is unknown.This study assessed the relationship between changes in NT-proBNP and the primary outcome (cardiovascular death or heart failure hospitalization); evaluated the effect of vericiguat on changes in NT-proBNP; and explored the association between the efficacy of vericiguat and changes in NT-proBNP.NT-proBNP was measured at randomization and at 16, 32, 48, and 96 weeks in 4,805 of 5,050 patients. The association between NT-proBNP change at week 16 and the primary outcome was assessed. The relationship between changes in NT-proBNP and the primary outcome according to treatment group was assessed by using joint modeling and mediation analysis.A significant and sustained decline in NT-proBNP levels was seen in both treatment groups. After week 16, NT-proBNP levels decreased more with vericiguat vs placebo (any reduction: odds ratio [OR]: 1.45 [95% CI: 1.28-1.65]; P 0.001; ≥50% reduction: OR: 1.27 [95% CI: 1.10-1.47]; P = 0.001) and were less likely to increase (≥20% increase: OR: 0.68 [95% CI: 0.59-0.78]; P 0.001; ≥50% increase: OR: 0.70 [95% CI: 0.59-0.82]; P 0.001). The treatment effect related to serial NT-proBNP on the primary composite outcome was HR: 0.96 (95% CI: 0.95-0.99) at week 16, which increased to HR: 0.90 (95% CI: 0.85-0.96) at week 48; the average extent of mediation of the composite outcome related to NT-proBNP was 45%.In patients with worsening HFrEF, vericiguat significantly decreased NT-proBNP levels compared with placebo. This change appeared associated with a modest relative improvement in the primary outcome of cardiovascular death or heart failure hospitalization. (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction [VICTORIA]; NCT02861534).

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.

Background In the VICTORIA trial of patients with HFrEF after a worsening HF event, anemia occurred more often in patients treated with vericiguat (7.6%) compared with placebo (5.7%). We explored the association between vericiguat, baseline hemoglobin, and anemia and also whether hemoglobin was related to the benefit of vericiguat in HF. Methods Anemia was defined as a hemoglobin Results Of 4812 patients with baseline hemoglobin data available, 1719 (35.7%) were WHO anemic; median hemoglobin was 13.4 g/dL (IQR 12.1 to 14.7 g/dL). In total, 1643 patients had WHO anemia at 16 weeks (of which 284 were new from baseline for vericiguat and 219 for placebo) and this occurred more often in the vericiguat group than the placebo group (P Conclusions Anemia was present at baseline in over one-third of patients in the VICTORIA trial and was generally mild. Lower hemoglobin was associated with greater frequency of clinical events. Although vericiguat modestly lowered hemoglobin by 16 weeks, this effect did not further progress nor influence the association of benefit of vericiguat. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Merck & Co., Inc. and Bayer

Introduction: People with type 2 diabetes mellitus (DM) have a large burden of cardiovascular (CV) morbidity and mortality, but the likelihood of these outcomes varies and existing risk calculators do not fully capture risk for individuals. Hypothesis: Circulating metabolites characterizing mitochondrial dysfunction may be novel predictors for CV outcomes. Methods: We performed targeted mass-spectrometry metabolite profiling (45 acylcarnitines, 15 amino acids) on baseline plasma samples from 568 cases (498 with major adverse cardiac events (MACE) and 131 with incident hospitalization for heart failure (hHF)) and 568 matched controls (without events) from the patients assigned to placebo in Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). Matching was based on history of HF, coronary artery disease, BMI, hemoglobin A1C, creatinine, low-density lipoprotein cholesterol, fasting status and ejection fraction. Principal components analysis (PCA) was used for dimensionality reduction, and conditional logistic regression to determine association of PCA factors with MACE or hHF and for individual metabolites within significant factors (false discovery rate q Results: Of 12 PCA-derived metabolite factors, three were associated significantly with MACE or hHF; these factors were composed of: 1) short-chain dicarboxylacylcarnitines and long chain acylcarnitines (OR 1.50, q=0.03); 2) medium chain acylcarnitines (OR 1.28, q=0.001); 3) C5:1 and one medium-chain dicarboxylacylcarnitine (OR 1.17, q=0.03). Of these three factors, none were significantly associated with the individual components of MACE. Ten individual metabolites, including short- and medium-chain dicarboxylacylcarnitines and medium- and long-chain acylcarnitines, remained significantly associated with MACE (q Conclusions: Metabolites reporting on dysregulated mitochondrial fatty acid oxidation and endoplasmic reticulum stress are elevated in individuals with DM who progress to MACE and/or hHF. These biomarkers may improve CV risk prediction in DM patients and help highlight emerging risk mechanisms.

Introduction: To date, there are limited data on the potential role of proteomic biomarkers to predict future cardiovascular (CV) events among patients with type 2 diabetes mellitus (DM). Hypothesis: Specific protein biomarkers will be predictive of major adverse CV events (MACE) and incident heart failure hospitalization (HFH) among patients with DM. Methods: Using the Olink aptamer-based platform, we performed proteomic profiling (>700 proteins) on 440 paired cases and matched controls from placebo-assigned participants in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). Cases were defined as having met the primary composite outcome of MACE or incident HFH and matched to controls on baseline prevalent heart failure, coronary artery disease, BMI, hemoglobin A1C, creatinine, low-density lipoprotein cholesterol, fasting status and ejection fraction. Conditional logistic regression was used to determine the association between log-transformed relative protein expression and incident MACE or HFH. False-discovery-rate (FDR) was used to adjust for multiple comparisons. Results: We identified three specific proteins that were significantly associated with prevalent MACE or HFH: METRNL, Notch 3, and ROR1 (OR 2.1, 1.6, 1.7 and q-value 0.01, 0.02, and 0.05 respectively) (Figure 1). METRNL, in particular, performed similarly to the established biomarker NT-proBNP (Figure 1). When MACE and HFH were analyzed separately, METRNL, in particular, remained strongly associated with both outcomes (OR 2.0, p Conclusions: Three novel protein biomarkers, in particular METRNL (a circulating adipokine that regulates insulin-sensitivity), may identify diabetic patients at high risk for subsequent HF and MACE. Additional studies are needed to replicate these findings and uncover the biologic mechanism linking adipokine signaling and heart failure.

Background There are limited data to inform policy mandating primary percutaneous coronary intervention ( PPCI ) volume benchmarks for catheterization laboratories in low‐ and middle‐income countries. Methods and Results This prospective state‐wide registry included ST‐segment–elevation myocardial infarction patients with symptoms of PPCI . From June 2013 to March 2016, we recruited 5560 consecutive patients. We categorized hospitals on the basis of annual PPCI volumes into low, medium, and high volume (PPCI volume and 1‐year mortality. Among 42 recruiting hospitals, there were 24 (57.2%) low‐volume, 8 (19%) medium‐volume, and 10 (23.8%) high‐volume hospitals. The median (25th–75th percentile) TIMI (Thrombolysis in Myocardial Infarction) ST‐segment–elevation myocardial infarction risk score was 3 (2–5). Cardiac arrest before admission occurred in 4.2%, 2.1%, and 2.9% of cases at low‐, medium‐, and high‐volume hospitals, respectively ( P =0.02). Total ischemic time differed significantly among low‐volume (median [25th–75th percentile], 3.5 [2.4–5.5] hours), medium‐volume (median, 3.8 [25th–75th percentile, 2.58–6.05] hours), and high‐volume hospitals (median, 4.16 [25th–75th percentile 2.8–6.3] hours) ( P =0.01). Vascular access was radial in 61.5%, 71.3%, and 63.2% of cases at low‐, medium‐, and high‐volume hospitals, respectively ( P =0.01). The observed 1‐year mortality rate was 6.5%, 3.4%, and 8.6% at low‐, medium‐ and high‐volume hospitals, respectively ( P CI ], 1.80 [1.12–2.90]; high versus medium: hazard ratio [95% CI ], 2.53 [1.78–3.58]) ( P Conclusions Low‐ and middle‐income countries, like India, may have a nonlinear relationship between institutional PPCI volume and outcomes, partly driven by procedural variations and inequalities in access to care.

Aims:The STREAM study randomly assigned ST-elevation myocardial infarction (STEMI) patients to receive a pharmacoinvasive versus primary percutaneous coronary intervention reperfusion strategy. We assessed whether there was an association between outcomes based on randomisation at a community hospital versus a prehospital location.Methods/results:Community hospital patients (358/1866 (19.2%)) were compared to prehospital patients and their outcomes categorised into pharmacoinvasive according to their treatment assignment. Compared to prehospital patients, community hospital patients had more diabetes (17.8% vs. 11.5%, P=0.001), higher Killip Class >1 (9.4% vs. 5.0%, P=0.002) and thrombolysis in myocardial infarction risk scores ⩾5 (18.2% vs. 12.4%, P=0.005). The 30-day primary endpoint (death, shock, congestive heart failure and re-infarction) for community hospital patients was 14.9% versus 13.2% for prehospital patients ( P=0.403). Community hospital pharmacoinvasive patients tended to receive less rescue (35.1% vs. 42.8%, P=0.062); when deployed their rescue was delayed 43 minutes. Community hospital patients undergoing primary percutaneous coronary intervention experienced a delay of 31 minutes versus prehospital patients. Pharmacoinvasive patients receiving scheduled angiography from a community hospital and prehospital patients had comparable times to angiography (17.7 vs. 18.7 hours) and low event rates (6.2% vs. 8.0%). Although the interaction between randomisation location and treatment received on the primary endpoint was not significant ( Pinteraction=0.065) those pharmacoinvasive patients requiring rescue from community hospitals had worse outcomes than prehospital rescue patients (odds ratio 2.28, 95% confidence interval 1.16–4.49).Conclusion:Within STREAM, STEMI patients randomly assigned at community hospitals had a higher baseline risk but similar outcomes compared to those studied prehospital patients irrespective of successful pharmacoinvasive therapy or primary percutaneous coronary intervention. However, worse outcomes in the pharmacoinvasive patients requiring rescue in community hospitals emphasises their need for immediate transfer to a percutaneous coronary intervention-capable hospital.

Background: Recent clinical trial data support a pharmacoinvasive strategy as an alternative to primary percutaneous coronary intervention (pPCI) in ST-segment elevation myocardial infarction. We evaluated whether this is true in a real-world prehospital ST-segment elevation myocardial infarction network using ECG assessment of reperfusion coupled with clinical outcomes within 1 year. Methods: Of the 5583 ST-segment elevation myocardial infarction patients in the Alberta Vital Heart Response Program (Cohort 1 [2006–2011]: n=3593; Cohort 2 [2013–2016]: n=1990), we studied 3287 patients who received a pharmacoinvasive strategy with tenecteplase (April 2013: half-dose tenecteplase was employed in prehospital patients ≥75 years) or pPCI. ECGs were analyzed within a core laboratory; sum ST-segment deviation resolution ≥50% was defined as successful reperfusion. The primary composite was all-cause death, congestive heart failure, cardiogenic shock, and recurrent myocardial infarction within 1 year. Results: The pharmacoinvasive approach was administered in 1805 patients (54.9%), (493 [27.3%] underwent rescue/urgent percutaneous coronary intervention and 1312 [72.7%] had scheduled angiography); pPCI was performed in 1482 patients (45.1%). There was greater ST-segment resolution post-catheterization/percutaneous coronary intervention with a pharmacoinvasive strategy versus pPCI (75.8% versus 64.3%, IP-weighted odds ratio, 1.59; 95% CI, 1.33–1.90; P P =0.033). Major bleeding and intracranial hemorrhage were similar between a pharmacoinvasive strategy and pPCI (7.6% versus 7.5%, P =0.867; 0.6% versus 0.6%; P =0.841, respectively). In the 82 patients ≥75 years with a prehospital pharmacoinvasive strategy, similar ST-segment resolution and rescue rates were observed with full-dose versus half-dose tenecteplase (75.8% versus 88.9%, P =0.259; 31.0% versus 29.2%, P =0.867) with no difference in the primary composite (31.0% versus 25.0%, P =0.585). Conclusions: In this large Canadian ST-segment elevation myocardial infarction registry, a pharmacoinvasive strategy was associated with improved ST-segment resolution and enhanced outcomes within 1 year compared with pPCI. Our findings support the application of a selective pharmacoinvasive reperfusion strategy when delay to pPCI exists.

Contains fulltext : 215191.pdf (Publisher’s version ) (Closed access) BACKGROUND: The effects of beta-blocker therapy in patients with type 2 diabetes (T2D) and established atherosclerotic cardiovascular disease (ASCVD) are unclear. We sought to evaluate associations between beta-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 beta-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 beta-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 beta-blocker use versus no beta-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 beta-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 beta-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 beta-blocker therapy in this patient population. (TECOS ClinicalTrials.gov number, NCT00790205).

Aim To examine fracture incidence among participants in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). Research design and methods We used data from 14 671 participants in the TECOS study who were randomized double-blind to sitagliptin (n = 7332) or placebo (n = 7339). Cumulative fracture incidence rates were calculated and their association with study treatment assignment was examined using multivariable Cox proportional hazards regression. Results The baseline mean (standard deviation) participant age was 65.5 (8.0) years, diabetes duration was 11.6 (8.1) years and glycated haemoglobin level was 7.2 (0.5)% [55.2 (5.5) mmol/mol], and 29.3% of participants were women and 32.1% were non-white. During 43 222 person-years’ follow-up, 375 (2.6%; 8.7 per 1000 person-years) had a fracture; 146 were major osteoporotic fractures (hip, n = 34; upper extremity, n = 81; and clinical spine, n = 31). Adjusted analyses showed fracture risk increased independently with older age (P < .001), female sex (P < .001), white race (P < .001), lower diastolic blood pressure (P < .001) and diabetic neuropathy (P = .003). Sitagliptin, compared with placebo, was not associated with a higher fracture risk [189 vs 186 incident fractures: unadjusted hazard ratio (HR) 1.01, 95% confidence interval (CI) 0.82 to 1.23, P = .944; adjusted HR 1.03, P = .745], major osteoporotic fractures (P = .673) or hip fractures (P = .761). Insulin therapy was associated with a higher fracture risk (HR 1.40, 95% CI 1.02-1.91; P = .035), and metformin with a lower risk (HR 0.76, 95% CI 0.59-0.98; P = .035). Conclusion Fractures were common among people with diabetes in the TECOS study, but were not related to sitagliptin therapy. Insulin and metformin treatment were associated with higher and lower fracture risks, respectively.

Background— Using a comprehensive ST-segment–elevation myocardial infarction registry, we evaluated the relationships of baseline Q waves, time from symptom onset, and reperfusion strategy with in-hospital clinical outcomes. Methods and Results— Consecutive ST-segment–elevation myocardial infarction patients from a defined health region were classified by the presence of baseline Q waves and additionally into primary percutaneous coronary intervention, fibrinolysis, or no reperfusion. ECGs were collected at baseline, after reperfusion, and analyzed for the presence of Q waves using Selvester criteria. Among 2290 ST-segment–elevation myocardial infarction patients, 36.9% had Q waves on their baseline ECG. Patients with Q waves were older (median age, 59 versus 57), were more often male (82.0% versus 75.4%), had higher heart rate (80 versus 72), had higher Global Registry of Acute Coronary Events risk score (129 versus 127), and were with longer time to reperfusion (42 minutes longer). They had higher composite end points (16.3% versus 10.0%), consistent across times from symptom onset to presentation (15.4% versus 9.9% ≤3 hours; 18.5% versus 8.9% >3 to ≤6 hours; 15.9% versus 11.3% >6 hours; Q and no Q, respectively). Baseline Q waves, but not time to reperfusion, were associated with an increased odds of the in-hospital composite end point of death, congestive heart failure, cardiogenic shock, and reinfarction (adjusted odds ratio, 1.65; 95% confidence interval, 1.18–2.30; P =0.003). Type of reperfusion did not modify the association of baseline Q waves and in-hospital outcomes ( P interaction=0.918). Conclusions— The presence of baseline Q waves, rather than time to treatment, was significantly associated with adverse in-hospital events in real-world patients, regardless of reperfusion strategy used.

The secondary prevention effects of beta-blocker therapy (BBT) in type 2 diabetes (T2D) and established atherosclerotic cardiovascular disease (ASCVD) are unclear. Using an inverse probability of treatment-weighted Cox proportional hazards model, we examined the association between baseline BBT and

Ticagrelor (TIC) based dual antiplatelet therapy (DAPT) is standard of care for acute coronary syndromes (ACS) with the exception of fibrinolysis treated ST-segment elevation myocardial infarction (STEMI) patients where clopidogrel (CLOP) is recommended. Although comparable 30-day safety was shown

Objective Type 2 diabetes is associated with increased fracture risk, further elevated by treatments such as thiazolidinediones and sodium-glucose co-transporter-2 inhibitors. As data regarding dipeptidyl peptidase-4 inhibitors are mixed, we examined fracture incidence in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). Research Design and Methods We used data from 14,671 TECOS patients randomized double-blind to sitagliptin (n=7332) or placebo (n=7339). Cumulative fracture incidence rates were calculated and their association with study treatment assignment examined using multivariable Cox proportional hazards regression. Results Baseline mean (SD) age was 65.5 (8.0) years, diabetes duration 11.6 (8.1) years, HbA1c 7.2% (0.5%) (55.2 mmol/mol [5.5]), with 29.3% of participants women and 32.1% non-White. During 43,222 person-years’ follow-up, 375 (2.6%; 8.7 per 1000 person-years) had a fracture; 146 were major osteoporotic fractures (hip [n=34], upper extremity [n=81], and clinical spine [n=31]). Adjusted analyses showed fracture risk increased independently with older age (p Conclusion Fractures were common among TECOS patients with diabetes, but not related to sitagliptin therapy. Insulin and metformin treatment were associated with increased and decreased fracture risks, respectively.

Background: Baseline Q waves may provide additional value compared with time from the onset of symptoms in predicting outcomes for patients with ST-segment elevation. We evaluated whether baseline Q waves superseded time from symptom onset as a prognostic marker of one-year mortality in patients with ST-segment elevation acute coronary syndrome. Our study was derived from data from patients undergoing primary percutaneous coronary intervention within 24 hours in the PLATelet inhibition and patient Outcomes trial Methods: Q waves on the baseline electrocardiogram were evaluated by a blinded core laboratory. We assessed the associations between baseline Q waves and time from symptom onset to percutaneous coronary intervention with peak biomarkers, ST-segment resolution on the discharge electrocardiogram, and one-year all-cause and vascular mortality. Results: Of 4341 patients with ST-segment elevation, 46% had baseline Q waves. Compared to those without Q waves, those with baseline Q waves were older, more frequently male, had higher heart rates, more advanced Killip class and had a longer time between the onset of symptoms and percutaneous coronary intervention. They also had higher one-year all-cause mortality than patients without baseline Q waves (baseline Q waves: 4.9%; no baseline Q waves: 2.8%; hazard ratio [HR] 1.78, 95% confidence interval [CI] 1.29–2.45, p p = 0.046) and vascular mortality (adjusted HR 1.58, 95% CI 1.09–2.28, p = 0.02). Interpretation: The presence of baseline Q waves provides useful additional prognostic insight into the clinical outcome of patients with ST-segment elevation. Clinical Trials.gov registration no. NCT00391872

Background Whether prehospital point‐of‐care ( POC ) troponin further accelerates the time to diagnosis in patients with chest pain ( CP ) is unknown. We conducted a randomized trial of POC ‐Troponin testing in the ambulance. Methods and Results Patients with chest pain presenting by ambulance were randomized to usual care ( UC ) or POC ‐Troponin; ST ‐elevation myocardial infarction patients or those with noncardiovascular symptoms were excluded. Pre‐hospital high‐sensitivity troponin was analyzed on a POC device and available to the paramedic and emergency department ( ED ) staff. The final diagnosis was centrally adjudicated. The primary endpoint was time from first medical contact to discharge from ED or admission to hospital. We randomized 601 patients in 19 months; 296 to UC and 305 to POC ‐Troponin. After ambulance arrival, the first troponin was available in 38 minutes in POC ‐Troponin and 139 minutes in UC . In POC ‐Troponin, the troponin was >0.01 ng/mL in 17.4% and >0.03 ng/mL in 9.8%. Patients spent a median of 9.0 hours from first medical contact to final disposition, and 165 (27.4%) were admitted to the hospital. The primary endpoint was shorter in patients randomized to POC ‐Troponin (median 8.8 hours [6.2–10.8] compared to UC (median 9.1 hours [6.7–11.2]; P =0.05). There was no difference in the secondary endpoint of repeat ED visits, hospitalizations, or death in the next 30 days. Conclusions In this broad population of patients with CP , ambulance POC ‐Troponin accelerated the time to final disposition. Enhanced and more cost‐effective early ED discharge of the majority of patients with CP calling 911 is an unrealized opportunity. Clinical Trial Registration URL : https://www.ClinicalTrials.gov/ . Unique identifier: NCT 01634425.

Objectives: The STREAM study randomized STEMI pts Methods: CH pts 358/1866 (19.2%) were compared to PH pts. Results are further categorized according to pts receiving pPCI, PI rescue, PI with scheduled angiography (%’s and medians with 25th-75th percentiles). Results: Overall compared to PH, CH pts had more diabetes (17.8% vs. 11.5%, p=0.001), higher Killip Class >1 (9.4% vs. 5.0%, p=0.002) and TIMI Risk Score ≥5 (18.2% vs. 12.4%, p=0.005). 30-day primary composite endpoint (death, CHF, shock, re-infarction) for CH was 14.9% vs. PH 13.2% (p=0.403). PI pts within CH received less rescue PCI than PH pts (35.1% vs. 42.8%, p=0.062) (table) and it was delayed by approximately 43 min. CH pts undergoing pPCI also had an approximate 31 min delay. After adjusting for TIMI risk score and time from symptom onset, CH pts requiring rescue had worse outcomes compared to PH (OR 2.3, 95% CI, 1.2-4.6); However no difference in outcomes existed between CH and PH pts in those undergoing pPCI (p interaction=0.027). PI pts receiving scheduled cath from CH and PH had comparable times to cath (17.7 vs. 18.7 hours) and low primary composite event rates (6.2% vs 8.0%). Conclusion: Within STREAM CH pts had higher baseline risk but overall similar outcomes to those randomized PH. Despite higher baseline risk, CH pts with successful fibrinolysis and scheduled angiography or those who underwent primary PCI had similar outcomes to PH. The worse outcomes in CH rescue pts emphasizes the need to identify and expeditiously treat those pts needing rescue PCI.

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. Assessment engineering (AE) is emerging as a new research area in educational and psychological measurement (Luecht, 2006a, 2006b). AE is an innovative approach to measurement, where engineering-like principles are used to direct the design and the analysis of assessments as well as the scoring and the reporting of the results. With this approach, an assessment begins with specific, empirically derived cognitive models (e.g., Leighton & Gierl, 2007). Next, assessment task templates are created using established frameworks derived from the cognitive model to produce test items. Finally, psychometric methods are applied to the examinee response data, typically in a confirmatory mode, to produce scores that are interpretable (Luecht, Gierl, Tan, & Huff, 2006). AE differs from more traditional approaches to test design and analysis in three fundamental ways. First, cognitive models guide task design and item development, rather than content-based test specifications. While the categories in content blueprints can be included in the task templates, the assessment principles used to develop items are based on cognitive principles and, thus, provide more specific information for measuring problem-solving skills. Second, task templates are created to control and manipulate both the content and cognitive attributes of the items. Item writers are required to use the templates during development, thereby producing items that adhere to strict quality controls and that meet high psychometric standards. Third, psychometric models are employed in a confirmatory, versus exploratory, manner to assess the model-data fit relative to the intended underlying structure of the constructs or traits the test is designed to measure. The outcomes from these model-data fit analyses also provide developers with guidelines for

Background A pharmacoinvasive ( PI ) strategy for early presenting ST ‐segment elevation myocardial infarction nominally reduced 30‐day cardiogenic shock and congestive heart failure compared with primary percutaneous coronary intervention ( PPCI ). We evaluated whether infarct size ( IS ) was related to this finding. Methods and Results Using the peak cardiac biomarker in patients randomized to PI versus PPCI within the Strategic Reperfusion Early After Myocardial Infarction ( STREAM ) trial, IS was divided into 3 groups: small (≤2 times the upper limit normal [ ULN ]), medium (>2 to ≤5 times the upper limit normal) and large (>5 times the upper limit normal). The association between IS and 30‐day shock and congestive heart failure was subsequently examined. Data on 1701 of 1892 (89.9%) patients randomized to PI (n=853, 50.1%) versus PPCI (n=848, 49.9%) within STREAM were evaluated. A higher proportion of PPCI patients had a large IS ( PI versus PPCI : small, 49.8% versus 50.2%; medium, 56.9% versus 43.1%; large, 48.4% versus 51.6%; P =0.035), despite comparable intergroup ischemic times for each reperfusion strategy. As IS increased, a parallel increment in shock and congestive heart failure occurred in both treatment arms, except for the small IS group. The difference in shock and congestive heart failure in the small IS group (4.4% versus 11.6%, P =0.026) in favor of PI likely relates to higher rates of aborted myocardial infarction with the PI strategy (72.7% versus 54.3%, P =0.005). After adjustment, a trend favoring PI persisted in this subgroup (relative risk 0.40, 95% CI 0.15 to 1.06, P =0.064); no difference in treatment‐related outcomes was evident in the other 2 groups. Conclusion A PI strategy appears to alter the pattern of IS after ST ‐segment elevation myocardial infarction, resulting in more medium and fewer large infarcts compared with PPCI . Despite a comparable number of small infarcts, PI patients in this group had more aborted myocardial infarctions and less 30‐day shock and congestive heart failure. Clinical Trial Registration URL : http://ClinicalTrials.gov . Unique identifier: NCT 00623623.

Background: Baseline Q waves on the initial 12-lead ECG in clinical trials has been shown to be a simple predictor of clinical outcomes in STEMI patients. Whether this relationship applies in real world STEMI care is unknown. Using a large comprehensive STEMI registry, we evaluated the relationships

Aims Several methods provide new insights into understanding clinical trial composite endpoints, using both conventional and novel methods. The TRILOGY ACS trial is used as a contemporary example to prospectively compare these methods side by side. Methods and results The traditional time-to-first-event, Andersen–Gill recurrent events method, win ratio, and a weighted composite endpoint (WCE) are compared using the randomized, active-control TRILOGY ACS trial. This trial had a neutral result and randomized 9326 patients managed without coronary revascularization within 10 days of their acute coronary syndrome to receive either prasugrel or clopidogrel and followed them for up to 30 months. The traditional composite, win ratio, and WCE demonstrated no significant survival advantage for prasugrel, whereas the Andersen–Gill method demonstrated a statistical advantage for prasugrel [hazard ratio (HR), 0.86 (95% CI, 0.72–0.97)]. The traditional composite used 73% of total patient events; 40% of these were derived from the death events. The win ratio used 66% of total events; deaths comprised 57% of these. Both Andersen–Gill and WCE methods used all events in all participants; however, with the Andersen–Gill method, death comprised 41% of the proportion of events, whereas with the WCE method, death comprised 64% of events. Conclusion This study addresses the relative efficiency of various methods for assessing clinical trial events comprising the composite endpoint. The methods accounting for all events, in particular those incorporating their clinical relevance, appear most advantageous, and may be useful in interpreting future trials. This clinical and statistical advantage is especially evident with long-term follow-up where multiple non-fatal events are more common. Clinical Trial Registration NCT00699998.

Objectives The aim of this study was to compare clinical outcomes, resource utilization, and health-related quality of life between Canadian and U.S. patients enrolled in ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure). A further aim was to supplement the within-trial analysis with a contemporaneous population-based comparison of all patients hospitalized with primary diagnoses of heart failure (HF) in the 2 countries. Background Little is known about intercountry differences in outcomes of patients with HF in Canada and the United States. Methods Trial patients consisted of 465 Canadian and 2,684 U.S. patients enrolled in ASCEND-HF. Population-level cohorts consisted of 1.9 million U.S. and 81,016 Canadians hospitalized for HF in 2007 and 2008. Results Canadian patients in ASCEND-HF were older, were more likely to be white, and had lower body weights and blood pressures than U.S. patients. Canadians also had lower baseline-adjusted odds of 30-day mortality (odds ratio: 0.46; 95% confidence interval: 0.23 to 0.92) and better health-related quality of life than U.S. patients. In both countries, trial patients differed significantly from population-level cohorts. In contrast to ASCEND-HF, unadjusted in-hospital mortality at the population level was significantly lower in the United States (3.4%) compared with Canada (11.1%) (p Conclusions Intercountry differences in outcomes of patients hospitalized with HF differed significantly between trial and population cohorts. Further study on how cardiac care is delivered in the 2 countries and how it influences the results of clinical trials and population-level outcomes, especially in the long term, is warranted. (A Study Testing the Effectiveness of Nesiritide in Patients With Acute Decompensated Heart Failure; NCT00475852 )

ECGs and accurate STEMI diagnosis (r1⁄4 0.482, p 20 ECGs read per week showed statistically significant improvement in accuracy (P 20 ECGs per week was shown to significantly improve STEMI diagnosis, regardless of underlying training. Increased training and paramedic exposure to ECG interpretation may improve STEMI diagnosis and decrease false positive CCL activation.