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Background: Composite endpoints for estimating treatment efficacy are routinely used in several therapeutic areas and have become complex in the number and types of component outcomes included. It is assumed that its components are of similar asperity and chronology between both treatment arms as well as uniform in magnitude of the treatment effect. However, these assumptions are rarely satisfied. Understanding this heterogeneity is important in developing a meaningful assessment of the treatment effect. Methods: We developed the Weighted Composite Endpoint (WCE) method which uses weights derived from stakeholder values for each event type in the composite endpoint. The derivation for the product limit estimator and the variance of the estimate are presented. The method was then tested using data simulated from parameters based on a large cardiovascular trial. Variances from the estimated and traditional approach are compared through increasing sample size. Results: The WCE method used all of the events through follow-up and generated a multiple recurrent event survival. The treatment effect was measured as the difference in mean survivals between two treatment arms and corresponding 95% confidence interval, providing a less conservative estimate of survival and variance, giving a higher survival with a narrower confidence interval compared to the traditional time-to-first-event analysis. Conclusions: The WCE method embraces the clinical texture of events types by incorporating stakeholder values as well as all events during follow-up. While the effective number of events is lower in the WCE analysis, the reduction in variance enhances the ability to detect a treatment effect in clinical trials. [ABSTRACT FROM AUTHOR]

Background Myocardial infarction with non-obstructive coronary arteries (MINOCA) is a known clinical conundrum with limited investigation. Using a large population-based cohort, we examined the incidence, demographic profile, use of evidence-based medicines (EBM) and clinical outcomes of MINOCA patients. Methods Patients hospitalized with a primary diagnosis of MI who underwent coronary angiography between 01/04/2002 and 31/03/2014 in Alberta, Canada, were included in the study. Comparisons were made between patients with MINOCA versus obstructive coronary disease (OCD). The primary composite endpoint was 1-year all-cause death or re-MI. Results Of 35,928 patients hospitalized with MI, 2092 (5.8%) had MINOCA. In-hospital mortality rate was 0.8% among MINOCA, and 2.7% among patients with OCD ( p  < 0.0001). At 6 months, cardiovascular EBM rates were significantly lower among MINOCA patients compared to OCD patients. One-year death/re-MI rate was 5.3% in MINOCA and 8.9% in patients with OCD (adjusted hazard ratio (AHR) 0.75, 95% confidence interval (CI) 0.62–0.92, p  < 0.0001). Five-year mortality rates were 10.9% in MINOCA and 16.0% in patients with OCD. Upon further stratification, 770 (36.8%) of MINOCA patients had no angiographic evidence of CAD (i.e. normal angiograms). EBM rates were even lower among these patients. One-year death/re-MI rate among these patients was 3.9% as compared to 6.1% among MINOCA patients with stenosis <50% (AHR 0.68, 95% CI 0.44–1.07, p  = 0.028). Conclusions The population-level incidence of MINOCA is approximately 5%. Despite their apparently benign anatomic findings, efforts must be made to improve secondary prevention strategies to reduce the burden of long-term adverse outcomes in this population. [ABSTRACT FROM AUTHOR]

Advances in cardiovascular medicine fueled by innovative clinical trials have dramatically improved the lives of patients worldwide. Commensurate with this progress has been a decline in morbid and mortal events. Accordingly, an increased propensity to collate patient outcomes in clinical trials has emerged that combines death and nonfatal complications into a single composite event. Despite the acknowledged benefits in trial efficiency from such an approach, this method assumes uniform directionality of each component, does not distinguish the relative clinical significance of each, and counts only the first occurrence of any event in the final tally within a conventional time to first event analysis. In this article, we evaluate the criticisms that have been leveled at this approach and provide an overview of recently published phase III cardiovascular trials using primary composite end points. We then explore what to anticipate from the large cohort of as-yet unpublished clinical trials in this arena. Last, we propose a variety of novel approaches that use composite end points and suggest a path forward to enhancing their use in future clinical trials. [ABSTRACT FROM AUTHOR]

Composite endpoints are commonly used in cardiovascular clinical trials. When using a composite endpoint a subject is considered to have an event when the first component endpoint has occurred. The use of composite endpoints offers the ability to incorporate several clinically important endpoint events thereby augmenting the event rate and increasing statistical power for a given sample size. One assumption of the composite is that all component events are of equal clinical importance. This assumption is rarely achieved given the diversity of component endpoints included. One means of adjusting for this diversity is to adjust the outcomes using severity weights determined a priori. The use of a weighted endpoint also allows for the incorporation of multiple endpoints per patient. Although weighting the outcomes lowers the effective number of events, it offers additional information that reduces the variance of the estimate. We created a series of simulation studies to examine the effect on power as the individual components of a typical composite were changed. In one study, we noted that the weighted composite was able to offer discriminative power when the component outcomes were altered, while the traditional method was not. In the other study, we noted that the weighted composite offered a similar level of power to the traditional composite when the change was driven by the more severe endpoints. [ABSTRACT FROM AUTHOR]

Objectives Primary percutaneous coronary intervention (P-PCI) is the preferred reperfusion option in ST-elevation myocardial infarction, but its benefits become attenuated as time to its potential delivery becomes prolonged. Based on the STrategic Reperfusion Early After Myocardial Infarction trial, we assessed the impact of increasing time delay on outcomes in patients randomised to a pharmacoinvasive strategy (PI) or P-PCI. Methods Thirty-day clinical outcomes were examined according to PCI-related delay (P-RD). Data from hospitals that enrolled >10 randomised patients were used and P-RD categorised as ≤55 min, >55-97 min and >97 min. Results Composite of death/congestive heart failure/ cardiogenic shock/myocardial infarction in PI and P-PCI arms occurred in 10.6% versus 10.3% (≤55 min, p=0.910); 13.9% versus 17.9% (>55-97 min, p=0.148) and 13.5% versus 16.2% (>97 min, p=0.470), respectively. While there was no worsening of outcomes for PI across the P-RD spectrum, this occurred in the P-PCI arm (p(trend)=0.038). For P-RD <55 min, fewer events tended to occur with P-PCI than PI. Conversely, as P-RD increased to >55 min, PI-assigned patients had better outcomes than P-PCI, suggesting an event-free advantage with PI as P-RD increased (p (interaction)=0.094). Analysing P-RD continuously showed that for every 10-min increment there was an increasing trend towards benefit among PI-assigned patients (p(interaction)=0.073). Conclusions As P-RD increased, PI outcomes became superior to P-PCI when P-RD is prolonged and exceeds guideline-mandated times. In such circumstances, a PI strategy may provide an alternative reperfusion option. Adverse time delays for delivery of P-PCI should be considered when evaluating reperfusion strategies. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether the beneficial and harmful effects of platelet glycoprotein IIb/IIIa receptor blockers in non-ST elevation acute coronary syndromes (NSTE-ACS) depend on age. Methods: A meta-analysis of six trials of platelet glycoprotein IIb/IIIa receptor blockers in patients with NSTE-ACS (PRISM, PRISM-PLUS, PARAGON-A, PURSUIT, PARAGON-B, GUSTO IV-ACS; n = 31 402) was performed. We applied multivariable logistic regression analyses to evaluate the drug effects on death or non-fatal myocardial infarction at 30 days, and on major bleeding, by age subgroups (<60, 60-69, 70-79, ⩾80 years). We quantified the reduction of death or myocardial infarction as the number needed to treat (NNT), and the increase of major bleeding as the number needed to harm (NNH). Results: Subgroups had 11 155 (35%), 9727 (31%), 8468 (27%) and 2049 (7%) patients, respectively. The relative benefit of platelet glycoprotein Ib/IIIa receptor blockers did not differ significantly (p=0.5) between age subgroups (OR (95% CI) for death or myocardial infarction: 0.86 (0.74 to 0.99), 0.90 (0.80 to 1.02), 0.97(0.86 to 1.10), 0.90 (0.73 to 1.16); overall 0.91 (0.86 to 0.99). ORs for major bleeding were 1.9 (1.3 to 2.8), 1.9 (1.4 to 2.7), 1 .6 (1.2 to 2.1) and 2.5 (1.5-4.1). Overall NNT was 105, and overall NNH was 90. The oldest patients had larger absolute increases in major bleeding, but also had the largest absolute reductions of death or myocardial infarction. Patients ⩾80 years had half of the NNT and a third of the NNH of patients <60 years. Conclusions: In patients with NSTE-ACS, the relative reduction of death or non-fatal myocardial infarction with platelet glycoprotein IIb/IIIa receptor blockers was independent of patient age. Larger absolute outcome reductions were seen in older patients, but with a higher risk of major bleeding. Close monitoring of these patients is warranted. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to develop 30-day and 1-year risk stratification models for non–ST-segment elevation acute coronary syndrome (NSTE-ACS) patients that incorporate quantitative ST-segment depression and novel biomarkers. Background: Several novel biomarkers have changed the risk profile of ACS; thus, the reassessment of traditional indicators such as ST-segment depression in this new context is warranted. Methods: Multivariable logistic regression was used to identify significant predictors of 30-day death and death/myocardial infarction (MI) and 1-year mortality in 7,800 NSTE-ACS patients enrolled in the GUSTO-IV (Global Utilization of Strategies to Open Occluded Arteries-IV ACS) trial between 1998 and 2000. Results: Among all other predictors, the degree of ST-segment depression had the highest prognostic value for 30-day death, 30-day death/MI, and 1-year death. Troponin T (TnT), creatinine clearance, N-terminal pro-brain natriuretic peptide (NT-proBNP), heart rate, and age were also highly influential on adverse outcomes. Unlike TnT and NT-proBNP, C-reactive protein was only predictive of long-term death. In contrast to mortality, the contribution of TnT to predicting 30-day death/MI increased, whereas NT-proBNP’s role was attenuated. The discriminatory power was excellent (c-index [adjusted for over-optimism]: 0.82 [30-day death]; 0.72 [30-day death/MI]; 0.81 [1-year]). Conclusions: In this large contemporary study of NSTE-ACS patients, novel insights into risk stratification were observed—in particular, the utility of quantitative ST-segment depression and multiple biomarkers. Collection of these indicators in future NSTE-ACS populations is recommended to evaluate generalizability and clinical application of these findings. [Copyright &y& Elsevier]

An introduction is presented in which the editors discuss a report within the issue related to the impact on Cardiovascular system diseases of adrenergic beta blockers ticagrelor and clopidogrel.

Aims Methods and results Conclusions Reverse ventricular remodelling, defined as a decrease in left ventricular end‐systolic volume indexed to body surface area (LVESVI) or an increase in left ventricular ejection fraction (LVEF), is associated with improved clinical outcomes in patients with heart failure with reduced ejection fraction (HFrEF). However, the underlying pathophysiological mechanisms remain unclear.We evaluated paired core‐lab assessed echocardiograms and measurements of 92 biomarkers at baseline and 8 months thereafter in 419 participants with HFrEF. Reverse ventricular remodelling was defined as a >5% LVEF increase or >15% LVESVI relative decrease between baseline and 8 months. We evaluated the association between baseline biomarkers and their changes with reverse ventricular remodelling in the prospectively randomized controlled VICTORIA (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction) trial. Of 419 patients (median age 66 [interquartile range 57–74] years, 27.4% women), 206 (49.2%) had reverse ventricular remodelling (either a 5% LVEF increase or a 15% LVESVI decrease). There were no differences in baseline biomarker concentrations between patients with versus those without reverse ventricular remodelling on follow‐up. However, in patients with reverse ventricular remodelling there were significant decreases in biomarkers relating to inflammation and cardiac metabolism; particularly the tumour necrosis factor superfamily member 13B (ratio 0.82, 95% confidence interval [CI] 0.77–0.88), growth differentiation factor‐15 (ratio 0.74, 95% CI 0.66–0.84), and insulin‐like growth factor binding protein 7 (ratio 0.80, 95% CI 0.73–0.88).Reverse ventricular remodelling in patients with HFrEF is associated with a decrease of biomarkers related to inflammation and cardiac metabolism. [ABSTRACT FROM AUTHOR]

Polytomous regression models generalize logistic models for the case of a categorical outcome variable with more than two distinct categories. These models are currently used in clinical research, and it is essential to measure their abilities to distinguish between the categories of the outcome. In 2012, van Calster et al proposed the polytomous discrimination index (PDI) as an extension of the binary discrimination c-statistic to unordered polytomous regression. The PDI is a summary of the simultaneous discrimination between all outcome categories. Previous implementations of the PDI are not capable of running on "big data." This article shows that the PDI formula can be manipulated to depend only on the distributions of the predicted probabilities evaluated for each outcome category and within each observed level of the outcome, which substantially improves the computation time. We present a SAS macro and R function that can rapidly evaluate the PDI and its components. The routines are evaluated on several simulated datasets after varying the number of categories of the outcome and size of the data and two real-world large administrative health datasets. We compare PDI with two other discrimination indices: M-index and hypervolume under the manifold (HUM) on simulated examples. We describe situations where the PDI and HUM, indices based on multiple comparisons, are superior to the M-index, an index based on pairwise comparisons, to detect predictions that are no different than random selection or erroneous due to incorrect ranking. [ABSTRACT FROM AUTHOR]

Aims: In VICTORIA, vericiguat compared with placebo reduced the risk of cardiovascular death (CVD) and heart failure hospitalization (HFH) in patients enrolled after a worsening heart failure (WHF) event. We examined clinical outcomes and efficacy of vericiguat as it relates to background use of loop diuretics in patients with WHF. Methods and results: We calculated the total daily loop diuretic dose equivalent to furosemide dosing at randomization and categorized these as: no loop diuretic, 1–39, 41–80, 40, and >80 mg total daily dose (TDD). The primary composite outcome of CVD/HFH and its components were evaluated based on TDD loop diuretic and expressed as adjusted hazard ratios with 95% confidence intervals. Post‐randomization rates of change in TDD were also examined. Of 4974 patients (98% of the trial) with diuretic dose information available at randomization, 540 (10.8%) were on no loop diuretic, 647 (13.0%) were on 1–39, 1633 (32.8%) were on 40, 1185 (23.8%) were on 41–80, and 969 (19.4%) were on >80 mg TDD. Patients with higher TDD had a higher rate of primary and secondary clinical outcomes. There were no significant interactions with TDD at randomization and efficacy of vericiguat versus placebo for any outcome (all pinteraction > 0.5). Post‐randomization diuretic dose changes for vericiguat and placebo showed similar rates of up‐titration (19.6 and 20.2/100 person‐years), down‐titration (16.8 and 18.1/100 person‐years), and stopping diuretics (22.9 and 24.2/100 person‐years). Conclusions: Loop diuretic TDD at randomization was independently associated with worse outcomes in this high‐risk population. The efficacy of vericiguat was consistent across the range of diuretic doses. [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]

Aim: Describe the distinguishing features of heart failure (HF) patients with reduced ejection fraction (HFrEF) in the VICTORIA (Vericiguat Global Study in Patients with Heart Failure with Reduced Ejection Fraction) trial.Methods and Results: Key background characteristics were evaluated in 5050 patients randomized in VICTORIA and categorized into three cohorts reflecting their index worsening HF event. Differences within the VICTORIA population were assessed and compared with PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and COMMANDER HF (A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants with Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure). VICTORIA patients had increased risk of mortality and rehospitalization: New York Heart Association class (40% class III), atrial fibrillation (45%), diabetes (47%), hypertension (79%) and mean estimated glomerular filtration rate of 61.5 mL/min/1.73 m2 . Baseline standard of HF care was very good: 60% received triple therapy. Their N-terminal pro-B-type natriuretic peptide was 3377 pg/mL [interquartile range (IQR) 1992-6380]. Natriuretic peptides were 30% higher level in the 67% patients with HF hospitalization <3 months, compared to those within 3-6 months of HF hospitalization and those randomized after recent outpatient intravenous diuretic therapy. Overall the median MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure) risk score in VICTORIA was 23 (IQR 18-27) as compared to the MAGGIC risk score in PARADIGM-HF of 20 (IQR 16-24).Conclusions: VICTORIA comprises a broadly generalizable high-risk population of three unique clinical strata of worsening chronic HFrEF despite very good HF therapy. VICTORIA will establish the role of vericiguat, a soluble guanylate cyclase stimulator, in HFrEF. [ABSTRACT FROM AUTHOR]

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]

BACKGROUND: ST-segment-elevation myocardial infarction (STEMI) guidelines recommend pharmaco-invasive treatment if timely primary percutaneous coronary intervention (PCI) is unavailable. Full-dose tenecteplase is associated with an increased risk of intracranial hemorrhage in older patients. Whether pharmaco-invasive treatment with half-dose tenecteplase is effective and safe in older patients with STEMI is unknown. METHODS: STREAM-2 (Strategic Reperfusion in Elderly Patients Early After Myocardial Infarction) was an investigatorinitiated, open-label, randomized, multicenter study. Patients =60 years of age with =2 mm ST-segment elevation in 2 contiguous leads, unable to undergo primary PCI within 1 hour, were randomly assigned (2:1) to half-dose tenecteplase followed by coronary angiography and PCI (if indicated) 6 to 24 hours after randomization, or to primary PCI. Efficacy end points of primary interest were ST resolution and the 30-day composite of death, shock, heart failure, or reinfarction. Safety assessments included stroke and nonintracranial bleeding. RESULTS: Patients were assigned to pharmaco-invasive treatment (n=401) or primary PCI (n=203). Median times from randomization to tenecteplase or sheath insertion were 10 and 81 minutes, respectively. After last angiography, 85.2% of patients undergoing pharmaco-invasive treatment and 78.4% of patients undergoing primary PCI had =50% resolution of ST-segment elevation; their residual median sums of ST deviations were 4.5 versus 5.5 mm, respectively. Thrombolysis In Myocardial Infarction flow grade 3 at last angiography was ?87% in both groups. The composite clinical end point occurred in 12.8% (51/400) of patients undergoing pharmaco-invasive treatment and 13.3% (27/203) of patients undergoing primary PCI (relative risk, 0.96 [95% CI, 0.62-1.48]). Six intracranial hemorrhages occurred in the pharmaco-invasive arm (1.5%): 3 were protocol violations (excess anticoagulation in 2 and uncontrolled hypertension in 1). No intracranial bleeding occurred in the primary PCI arm. The incidence of major nonintracranial bleeding was low in both groups (<1.5%). CONCLUSIONS: Halving the dose of tenecteplase in a pharmaco-invasive strategy in this early-presenting, older STEMI population was associated with electrocardiographic changes that were at least comparable to those after primary PCI. Similar clinical efficacy and angiographic end points occurred in both treatment groups. The risk of intracranial hemorrhage was higher with half-dose tenecteplase than with primary PCI. If timely PCI is unavailable, this pharmaco-invasive strategy is a reasonable alternative, provided that contraindications to fibrinolysis are observed and excess anticoagulation is avoided. [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]

Abstract: Background: We evaluated whether electrocardiogram (ECG) characteristics were aligned with clinical outcomes and the effect of ticagrelor within the diverse spectrum of non-ST-elevation acute coronary syndrome patients enrolled in the PLATelet inhibition and patient Outcomes (PLATO) trial. Methods: There were 8884 PLATO patients who had baseline ECGs assessed by a core laboratory; of these, 4935 had an ECG at hospital discharge that also was assessed. Associations with study treatment on vascular death or myocardial infarction within 1 year were examined. Results: At baseline, most patients had either no or ≤0.5 mm of ST-segment depression (57%); 26% had 1.0 mm, and 17% had more extensive depression (>1.0 mm). Across the baseline ST-segment depression strata, there was a consistent treatment benefit with ticagrelor versus clopidogrel on vascular death/myocardial infarction. The extent of residual ST-segment depression at discharge was similar in the treatment groups, and the treatment effect did not differ by the extent of discharge ST-segment depression. There was a progressive increase in vascular death/myocardial infarction with increasing extent of baseline ST-segment depression (1.0 mm [vs no/0.5 mm]: hazard ratio [HR] 1.22; 95% confidence interval [CI], 1.03-1.45; >1.0 mm: HR 1.49; 95% CI, 1.24-1.78; P <.001) and at discharge (HR 1.28; 95% CI, 1.02-1.61; HR 2.13; 95% CI, 1.54-2.95; P <.001). Conclusion: The treatment effect of ticagrelor among non-ST-segment-elevation acute coronary syndrome patients was consistently expressed across all baseline ST-segment depression strata. There was no indication of an anti-ischemic benefit of ticagrelor as reflected on the discharge ECG. Our data affirm the independent prognostic relationship of both baseline and hospital discharge ST-segment depression on outcomes within 1 year in non-ST-segment-elevation acute coronary syndrome patients. [Copyright &y& Elsevier]

A response by Adrian V. Hernandez and colleagues is presented to a letter to the editor about their article on the effects of glycoprotein llb/llla inhibitors in patients with an acute coronary syndrome.

Aim: We assessed a subset of the 5040 patients in VICTORIA receiving sacubitril/valsartan, either at randomization (n = 731) or post-randomization drop-in use (n = 425), to evaluate the relationship between the efficacy and safety of combination therapy with vericiguat.Methods and Results: The efficacy of vericiguat on the primary composite endpoint, heart failure (HF) hospitalization, and all-cause mortality was assessed. Safety outcomes included symptomatic hypotension, syncope, worsening renal function, and hyperkalaemia. At randomization, 731 patients received sacubitril/valsartan; they were more frequently from Western Europe or North America, had lower ejection fraction and systolic blood pressure, and more use of triple background HF therapy (65.9% vs. 58.6%), biventricular pacemakers (17.9% vs. 14.1%), or implantable cardioverter defibrillators (42.3% vs. 25.3%). For patients on versus not on sacubitril/valsartan at randomization, adjusted hazard ratios (95% confidence intervals) for vericiguat's treatment effect on the primary composite outcome, cardiovascular death, and HF hospitalization were 0.92 (0.71-1.19) versus 0.89 (0.80-0.98), 0.71 (0.45-1.12) versus 0.95 (0.82-1.11), and 0.98 (0.74-1.29) versus 0.87 (0.78-0.98), respectively. No significant interaction existed between sacubitril/valsartan and vericiguat's treatment effect (p-values for interaction: 0.81, 0.23 and 0.47, respectively). Post-randomization, more drop-in sacubitril/valsartan use occurred in those assigned to placebo (n = 238) versus vericiguat (n = 187) (p = 0.007). Symptomatic hypotension (21.0% vs. 23.1%; p = 0.41), renal dysfunction (29.9% vs. 31.9%; p = 0.50), and hyperkalaemia (10.3% vs. 7.9%; p = 0.20) in patients receiving sacubitril/valsartan (n = 992) for ≥3 months were not different by treatment arm.Conclusions: Concomitant use of sacubitril/valsartan for at least 3 months did not alter the efficacy of vericiguat and was similarly safe and tolerated in both study arms. Sacubitril/valsartan was initiated more frequently after randomization in patients assigned to placebo versus vericiguat.Clinical Trial Registration: ClinicalTrials.gov NCT02861534. [ABSTRACT FROM AUTHOR]

Introduction: Given the rising prevalence of heart failure (HF), our objective is to explore the relationships between meteorological events and acute HF (AHF) globally. Methods: We used data from 30 countries participating in the ASCEND-HF trial. Parameters including temperature were normalized by location for the 37 days prior to the HF event. Meteorological events were classified as a change that occurred < 10% compared to baseline. The 7 days prior to the HF event was subdivided: T1: the day of and − 1 day; T2: 2 and 3 days; T3: 4 and 5 days; and T4: 6 and 7 days. Results are reported as ratios of observed to expected weather events at the time of AHF presentation. Results: From 7141 patients, median age was 67 (IQR 56–76) with 66% male patients and 60% of patients with ischemic cardiomyopathy. In T1, temperatures were warmer than expected with 10% fewer decreases in average [OR 0.91 95% CI (0.83–0.98)] and minimum [OR 0.90 95% CI (0.82–0.97)] temperature. In T2, temperatures were again warmer than expected with an excess number of increases in maximum [OR 1.18 95% CI (1.06–1.30)] and average [OR 1.21 95% CI (1.10–1.32)] temperature. In T4 temperatures were cooler than baseline with fewer increases [OR 0.84 95% CI (0.74–0.95)] in average temperature. Conclusions: Meteorological fluctuations appear most relevant in the 3 days (T1 and T2) prior to the HF hospitalization with temperature demonstrating a bidirectional relationship with AHF. Continued validation of biometeorological trends in HF will contribute to healthcare system planning globally. [ABSTRACT FROM AUTHOR]

Although a fibrinolytic pharmacoinvasive strategy is recommended for patients with ST elevation myocardial infarction (STEMI) unable to undergo timely primary percutaneous coronary intervention (PCI), there are limited data addressing outcomes specific to those with successful or unsuccessful pharmacologic reperfusions. Accordingly, we evaluated a contemporary pharmacoinvasive strategy for failed and successful reperfusions within the STrategic Reperfusion Early After Myocardial infarction study. Of 1,823 per-protocol-treated patients with STEMI, we examined clinical outcomes and angiographic and electrocardiographic metrics in 3 groups as follows: fibrinolysis requiring rescue (rescue, n = 348), fibrinolysis with scheduled angiography (scheduled, n = 516), and primary PCI (n = 927). Compared with pharmacoinvasive patients undergoing scheduled angiography, rescue patients were more likely to have anterior wall myocardial infarction, more baseline ST-segment elevation and deviation, as well as Q waves in the distribution of their ST elevation. Residual ST elevation ⩾2 mm 30 minutes after angiography occurred in 27.9%, 7.9%, and 24.8% of patients who underwent rescue, scheduled, and primary PCI, respectively. Thirty-day composite event rates (all-cause death, cardiogenic shock, heart failure, and reinfarction) were 18.7%, 5.5%, and 13.9%; all-cause death: 6.1%, 2.1%, and 3.9%; cardiogenic shock: 7.5%, 2.0%, and 5.4%; heart failure: 11.8%, 2.3%, and 7.6%; and reinfarction: 1.5%, 1.4%, and 2.2%, for rescue, scheduled, and primary PCI, respectively. Compared with successfully reperfused patients undergoing scheduled angiography, the adjusted relative risk of the primary outcome was 2.92 (95% confidence interval 1.92 to 4.45) in rescue patients. In conclusion, pharmacoinvasive-treated patients requiring rescue angiography had greater baseline risk with more co-morbidities and worse 30-day outcomes compared with successful fibrinolytic-treated patients. Residual ST elevation after reperfusion assists in defining prognosis. [ABSTRACT FROM AUTHOR]

Abstract: Background: Considerable uncertainty exists concerning the interaction between climate and human health. We explored this issue by evaluating the relationship between meteorological events and acute coronary syndrome (ACS) events. Methods: 9406 patients in 29 countries at 440 Early versus Delayed, Provisional Eptifibatide in Acute Coronary Syndromes (EARLY ACS) clinical trial sites were linked to a weather station by location. Temperature, barometric pressure, precipitation, wind speed and combined temperature and relative humidity were normalized by location for the 37days prior to the index ACS event that precipitated study enrollment. A meteorological event was defined as a change in any weather metric that was expected to occur in less than 10% of the exposure intervals: four separate 48-hour intervals within the seven days prior to an ACS event (T1, day of event and −1day; T2, −2 to −3days; T3, −4 to −5days; and T4, −6 to −7days). Results are reported as ratio of observed to expected events for the meteorological parameter. Results: There were 10% more drops in temperature observed in T4 (95%CI: 3–17%), and more increases in temperature observed during T1 (4%; 95%CI −2–9%). An excess number of wind speed increases (9%;95%CI 2–16%) and relative humidity increases (6%; 95%CI 0.1–14%) occurred during T4. Additionally, female patients in this cohort presented less often than male patients following drops in average temperature. Conclusions: Using a new method for integrating meteorological data into a clinical trial dataset, we identified associations between changes in weather conditions and the likelihood of an ACS event. [Copyright &y& Elsevier]

Q waves have been shown to be a stronger prognostic marker than time from symptom onset to percutaneous coronary intervention (PCI) in ST-segment elevation myocardial infarction. We examined whether the relative importance of these 2 measurements is modulated by patient gender. Q waves in the area of ST-segment elevation on baseline electrocardiogram were evaluated at a central core laboratory in 4,530 patients with ST-segment elevation myocardial infarction (3,468 men and 1,062 women) without previous infarction and who underwent PCI in the Assessment of Pexelizumab in Acute Myocardial Infarction (APEX-AMI) trial. Women were older and had higher rates of diabetes, hypertension, Killip class >I, and lower creatinine clearance compared to men. Time from symptom onset to PCI >3 hours was associated with a trend toward worse 90-day mortality (adjusted hazard ratio 1.5, 95% confidence interval 0.9 to 2.2) in men but not in women (0.8, 0.5 to 1.4). In contrast, presence of Q waves on baseline electrocardiogram was associated with significantly higher 90-day mortality in men (adjusted hazard ratio 1.7, 95% confidence interval 1.0 to 2.7) and women (2.3, 1.2 to 4.2). In conclusion, in this gender-specific analysis, baseline Q wave was found be a better marker of risk of 90-day mortality than time from symptom onset to PCI, overall, and especially in women. [Copyright &y& Elsevier]

The prognostic value of myocardial infarct size estimation by QRS scoring in patients with ST-segment elevation myocardial infarction (STEMI) who undergo primary percutaneous coronary intervention (PCI) is unclear. The standard 32-point Selvester QRS score on the discharge electrocardiogram (each point ∼3% left ventricular mass) was calculated in 4,113 patients with STEMI who underwent primary PCI and survived to hospital discharge in the APEX-AMI trial. QRS scores were divided into tertiles, i.e., ≤3 (<10% myocardium), 4 to 7 (10% to 21% myocardium), and ≥8 (>21% myocardium). Adjusted associations between QRS score and 90-day outcomes (death and composite of death/congestive heart failure (CHF)/shock) were examined. Higher QRS scores were associated with male gender, higher heart rate, worse Killip class, noninferior infarct location, greater ST-segment deviation, and longer times to reperfusion. Higher QRS scores were also associated with impaired culprit artery flow before and after PCI and more frequent multivessel disease. Adverse outcomes occurred more often in patients with higher QRS scores (90-day death: 1.9%, QRS score 0 to 3; 3.4%, 4 to 7; 4.9%, ≥8; 90-day death/shock/CHF: 4.5%, 0–3; 7.8%, 4 to 7; 12.1%, ≥8). After multivariable adjustment, patients with higher QRS scores remained more likely to develop an adverse outcome versus those with QRS scores ≤3 (score 4 to 7, hazard ratios [HR] for death 2.08, 95% confidence interval [CI] 1.26 to 3.41; HR for death/CHF/shock 2.00, 95% CI 1.26 to 3.17; score ≥8, HR for death 2.57, 95% CI 1.56 to 4.24, HR for death/CHF/shock 2.93, 95% CI 1.84 to 4.67). In conclusion, infarct size as estimated by QRS scoring at hospital discharge is an independent and prognostically relevant metric in patients with STEMI undergoing primary PCI. [ABSTRACT FROM AUTHOR]

Objectives: We assessed the incremental value of baseline Q waves over time from symptom onset as a marker of clinical outcome in ST-segment elevation myocardial infarction (STEMI). Background: Time from symptom onset is a central focus in STEMI patients. The presence of Q waves on the baseline electrocardiogram (ECG) has been suggested to be of incremental value to time from symptom onset in evaluating clinical outcomes. Methods: We evaluated baseline Q waves and ST-segment resolution 30 min after primary percutaneous intervention (PCI) ECGs in 4,530 STEMI patients without prior infarction. Additionally, peak biomarkers; 90-day mortality; and the composite of death, congestive heart failure (CHF), or cardiogenic shock were assessed. Results: Fifty-six percent of patients had baseline Q waves: they were older, more frequently male and diabetic, and had a more advanced Killip class. Patients with baseline Q waves had greater mortality and a higher composite rate of death, CHF, and shock versus patients without baseline Q waves at 90 days (5.3% vs. 2.1% and 12.1% vs. 4.8%, respectively, both p < 0.001). Complete ST-segment resolution was highest, whereas 90-day mortality and the composite outcome were lowest among those randomized ≤3 h without baseline Q waves. After multivariable adjustment, baseline Q-wave but not time from symptom onset was significantly associated with a 78% relative increase in the hazard of 90-day mortality and a 90% relative increase in the hazard of death, shock, and CHF. Conclusions: Baseline Q waves in STEMI patients treated with primary PCI provide an independent prognostic marker of clinical outcome. These data might be useful in designing future clinical trials as well as in evaluating patients for triage and potential transfer for planned primary PCI. (Pexelizumab in Conjunction With Angioplasty in Acute Myocardial Infarction [APEX-AMI]; NCT00091637) [Copyright &y& Elsevier]

Background: Previous studies examining sex-related differences in the treatment of coronary artery disease have focused on patients in hospital. We sought to examine sexrelated differences at an earlier point in care - presentation to the emergency department. Methods: We collected data on ambulatory care and hospital admissions for 54 134 patients (44% women) who presented to an emergency department in Alberta between July 1998 and March 2001 because of acute myocardial infarction, unstable angina, stable angina or chest pain. We used logistic regression and Cox regression analyses to determine sexspecific associations between the likelihood of discharge from the emergency department or coronary revascularization within 1 year and 1-year mortality after adjusting for age, comorbidities and socioeconomic factors. Results: Following the emergency department visit, 91.3% of patients with acute myocardial infarction, 87.4% of those with unstable angina, 40.7% of those with stable angina and 19.8% of those with c st pain were admitted to hospital. Women were more likely than men to be discharged from the emergency department: adjusted odds ratio (and 95% confidence interval [CI]) 2.25 (1.75-2.90) for acute myocardial infarction, 1.71 (1.45-2.01) for unstable angina, 1.33 (1.15-1.53) for stable angina and 1.46 (1.36-1.57) for chest pain. Women were less likely than men to undergo coronary revascularization within 1 year: adjusted odds ratio (and 95% CI) 0.65 (0.57-0.73) for myocardial infarction, 0.39 (0.35-0.44) for unstable angina, 0.35 (0.29-0.42) for stable angina and 0.32 (0.27-0.37) for chest pain. Female sex had no impact on 1-year mortality among patients with acute myocardial infarction; it was associated with a decreased 1-year mortality among patients with unstable angina, stable angina and chest pain: adjusted hazard ratio (and 95% CI) 0.60 (0.46-0.78), 0.60 (0.46-0.78) and 0.74 (0.63-0.87) respectively. Interpretation: Women presenting to the emergency department with coronary syndromes are less likely than men to be admitted to an acute care hospital and to receive coronary revascularization procedures. These differences do not translate into worse outcomes for women in terms of 1-year mortality. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To assess the effects of socioeconomic status on mortality in patients with acute myocardial infarction. Material and Methods: We studied a retrospective cohort of 5622 patients who presented to a hospital emergency department with an initial episode of acute myocardial infarction between April 1998 and March 2002 in the Province of Alberta, Canada. Our main outcome measure was 1-year all-cause mortality following the index emergency department visit; we used socioeconomic status (measured by neighborhood median household income) as our main predictor after controlling for patient and hospital characteristics and revascularization. Results: Socioeconomic status profoundly affected the rate of emergency department presentation and the process and outcome of acute myocardial infarction care. In patients belonging to the lowest versus the highest socioeconomic status quartile, the risk of presenting to the emergency department was 72% higher (P <.001); at 1 year, revascularization was lower (36% vs 48%, P <.001), and mortality higher (19.1% vs 9.1%, P <.001). Socioeconomic status was independently associated with 1-year mortality after adjustment for baseline characteristics and 1-year revascularization, and socioeconomic status was especially influential in non-revascularized patients. Conclusions: Given the influence of socioeconomic status on mortality after acute myocardial infarction and the key role of revascularization in modulating this relationship, our study has important implications for access to and process of cardiac care. [Copyright &y& Elsevier]

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]

: PurposeTo assess the potential long-term beneficial effects of statin use after successful abdominal aortic surgery.: MethodsBetween 1991 and 2001, 570 patients underwent abdominal aortic aneurysm repair at the Erasmus Medical Center. Of the 519 patients (91%) who survived surgery beyond 30 days, 510 (98%) were followed for a median of 4.7 years (interquartile range, 2.7 to 7.3 years). These patients were evaluated for use of statins and beta-blockers, and for clinical risk factors (e.g., advanced age; prior myocardial infarction; diabetes mellitus; renal dysfunction; chronic pulmonary disease; history of heart failure, stroke, or angina), and their association with all-cause and cardiovascular mortality.: ResultsA total of 205 patients (40%) died during follow-up; 140 due to cardiovascular causes. The incidence of all-cause (18% [27/154] vs. 50% [178/356], P <0.001) and cardiovascular (11% [17/154] vs. 34% [122/356], P <0.001) mortality was significantly lower in statin users than in nonstatin users. After adjusting for clinical risk factors and beta-blocker use, the association between statin use and reduced all-cause (hazard ratio [HR] = 0.4; 95% confidence interval [CI]: 0.3 to 0.6; P <0.001) and cardiovascular (HR = 0.3; 95% CI: 0.2 to 0.6; P <0.001) mortality persisted. Beta-blocker use was also associated with a significant reduction in all-cause (HR = 0.6; 95% CI: 0.5 to 0.9; P = 0.003) and cardiovascular (HR = 0.7; 95% CI: 0.4 to 0.9; P = 0.03) mortality. There was no evidence of an association between statin use and all-cause and cardiovascular mortality according to beta-blocker use or clinical risk factors.: ConclusionLong-term statin use is associated with reduced all-cause and cardiovascular mortality irrespective of clinical risk factors and beta-blocker use. [Copyright &y& Elsevier]

Background: In the VICTORIA trial, anemia occurred more often in patients treated with vericiguat (7.6%) than 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 <13.0 g/dL in men and <12.0 g/dL in women (World Health Organization [WHO] Anemia). Adverse events (AEs) reported as anemia were also evaluated. We assessed the risk-adjusted relationship between hemoglobin and hematocrit with the primary outcome (composite of cardiovascular death or heart failure hospitalization), and the time-updated hemoglobin relationship to outcomes. Results: At baseline, 1719 (35.7%) had WHO 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 WHO anemia (284 new for vericiguat and 219 for placebo), which occurred more often with vericiguat than placebo (p<0.001). After 16 weeks, no further decline in hemoglobin occurred over 96 weeks of follow-up and the ratio of hemoglobin/hematocrit remained constant. Overall, AE anemia occurred in 342 patients (7.1%). A lower hemoglobin was unrelated to the treatment benefit of vericiguat (vs. placebo) on the primary outcome. Additionally, analysis of time-updated hemoglobin revealed no association with the treatment effect of vericiguat (vs. placebo) on the primary outcome. 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. Clinical Trial Registration: Clinical Trials.gov (NCT02861534). [ABSTRACT FROM AUTHOR]

Background: Patient sex has been shown to differentially affect mortality from unstable angina (UA) and acute myocardial infarction (AMI). However, to our knowledge, no prior population-based studies have examined both cohorts simultaneously to explain this intriguing variation. Hence, we undertook to explore and explain sex differences in 5-year mortality after UA and AMI. Methods: We used an administrative database of 22 967 patients with AMI and 8441 patients with UA discharged from acute care hospitals in Alberta between April 1, 1993, and March 31, 2000. Results: Women were older with more baseline comorbidities, more frequently had a diagnosis of UA, and had 30% lower relative odds of undergoing revascularization than men. Kaplan-Meier estimates of 5-year mortality were similar between sexes after UA (women vs men, 21.6% vs 19.5%; P = .09) but markedly higher for women after AMI (38.5% vs 26.6%, P<.001). After adjustment for baseline characteristics and revascularization, the hazard ratios (95% confidence intervals) for women vs men were 0.81 (0.72-0.92) after UA and 0.99 (0.93-1.05) after AMI. Only women younger than 65 years were at a significantly higher risk after AMI. The reasons for this difference in sex-related outcomes between UA and AMI may relate to greater disparities in the AMI cohort with respect to age, comorbidities, neighborhood incomes, and referrals to cardiovascular specialists. Conclusions: Relative to UA, AMI has a more serious impact on women than men, such that women have a survival advantage when afflicted with UA but lose that advantage with AMI. Additional investigation into the causes, treatment, and policy implications of the age-sex interaction is warranted. [ABSTRACT FROM AUTHOR]

Background We examined variation in hospital treatment and its relationship to clinical outcome in a large population-based cohort of ACS patients within a single payer-government funded health care system. Methods Patients hospitalized in 106 hospitals in Alberta, Canada with a primary diagnosis of ACS were included (July 1, 2010–March 31, 2013) with comparisons made across the three cardiac catheterization-capable hospitals (Sites A–C). Cox proportional-hazard regression models were used to examine the multivariable-adjusted association between site and 1-year death or repeat cardiovascular (CV) hospitalization (primary endpoint). Results Of 14,155 patients, 1938 (13.7%) were admitted to a community hospital without transfer to an invasive hospital (10.7% in-hospital death). The remaining were admitted ( n = 4514, 36.9%) or transferred ( n = 7703, 63.1%) to an invasive hospital (A:5480; B:3621; C:3116) where 11,247 (92.1%) underwent catheterization. Comorbidities and angiographic disease burden differed across sites. Variation in 30-day revascularization (PCI: 71.3%, 72.0%, 68.7%, p < 0.001; CABG: 6.2%, 6.4%, 9.3%, p < 0.001) and drug-eluting stent use for PCI (24.3%, 54.6%, 50.5%, p < 0.001) were observed. After adjustment for patient demographics and comorbidities, variation in rates of 1-year death or CV hospitalization was observed among those with 30-day revascularization (p(interaction) < 0.001; B versus A: HR 0.78, 95%CI 0.66–0.91; C versus A: HR 0.77, 95%CI 0.65–0.91; B versus C: HR 1.01, 95%CI 0.84–1.21). Conclusions Despite a government funded health system, we have shown variation in hospital treatment exists. Following adjustment hospital site was associated with differences in clinical outcome within 1 year. Hence, further efforts may be warranted to help address potential disparities in ACS care. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: Uncertainty exists concerning the relative merits of pharmacological versus mechanical coronary reperfusion in patients presenting early with ST-elevation myocardial infarction (STEMI) with extensive myocardium at risk. Accordingly, we investigated whether the extent of baseline ST-segment shift was related to the response of either reperfusion modality in patients with STEMI presenting within 3 h of symptoms.Methods: We analysed baseline ECGs from 1859 patients enrolled in the STrategic Reperfusion Early After Myocardial Infarction (STREAM) trial. The sum of ST-segment elevation (∑STE) and ST-segment deviation (∑STD) was categorised into quartiles and associations with the primary endpoint (30-day death/shock/congestive heart failure/re-myocardial infarction) for each reperfusion strategy (early fibrinolysis vs primary percutaneous coronary intervention) were explored.Results: Overall, there was a progressive rise in the 30-day primary endpoint according to quartiles of baseline ∑STE (10.3% (0-5 mm), 12.4% (5.5-8.5 mm), 12.1% (9-13.5 mm), 17.6% (> 14.0 mm), p = 0.008) and ∑STD (9.0% (0-9 mm), 13.5% (9.5-14 mm), 14.7% (14.5-20 mm), 15.3% (> 20 mm), p = 0.019). Both ∑STE and ∑STD were associated with the primary endpoint (∑STE: p = 0.071; ∑STD: p = 0.024). However, there was no interaction between quartiles of baseline ∑STE or ∑STD and efficacy of either reperfusion strategy on the 30-day clinical outcomes (∑STE: p (interaction) = 0.696; ∑STD: p (interaction) = 0.542).Conclusions: These data demonstrate an association between ∑STE or ∑STD on the baseline ECG and clinical events at 30 days following reperfusion therapy in STEMI. More importantly, the response to different reperfusion strategies was not influenced by the extent of jeopardised myocardium.Trial Registration Number: NCT00623623; Post-results. [ABSTRACT FROM AUTHOR]

Background: Randomised controlled trials have demonstrated improved outcomes with an early invasive strategy compared with routine care after fibrinolysis among patients with ST-elevation myocardial infarction. However, it remains uncertain whether specific patient subsets derive differential benefit from an early invasive strategy.Methods: Using patient-level data from seven randomised trials, we studied the relationship between treatment assignment (early invasive vs standard care) and adverse cardiovascular events. The outcomes assessed were death/reinfarction at 30 days and at 1 year, as well as death/reinfarction/recurrent ischaemia, major bleeding and stroke at 30 days. The analyses were conducted in strata (age, sex, diabetes, prior infarction, Killip class, anterior infarction and time from symptom onset to fibrinolysis) to assess for an interaction between the stratifying variable and treatment assigned.Results: There were 101 deaths and 115 recurrent infarctions at 30 days in 3010 patients. There were no strata where an invasive strategy conferred a differential treatment effect. With the exception of a marginally significant interaction between Killip class and treatment for death/reinfarction at 30 days and 1 year (p values for interaction 0.044 and 0.038, respectively), no interactions between the stratifying variables and treatment assignment were observed.Conclusions: Benefit from an early invasive strategy after fibrinolysis for ST-elevation myocardial infarction is similar across patient subgroups stratified by these clinical characteristics. Therefore, prediction of risk and benefit from an early invasive strategy after fibrinolysis for ST-elevation myocardial infarction is best achieved by global risk evaluation rather than specific patient characteristics. [ABSTRACT FROM AUTHOR]

Background: Little is known about global patterns of critical care unit (CCU) care and the relationship with outcomes in patients with acute decompensated heart failure (ADHF). Whether a ward or a CCU admission is associated with better outcomes is unclear. Methods: Patients in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial were initially hospitalized in a ward or CCU (coronary or intensive care unit). Sites were geographically classified: Asia-Pacific (AP), Central Europe (CE), Latin America (LA), North America (NA), and Western-Europe (WE). The primary outcome of 30-day all-cause mortality or all-cause hospital readmission was adjusted using a two-stage multivariable logistic regression model with a generalized estimated equation that took sites within each country as a nested random factor. Results: Overall, 1944 (38.2%) patients were admitted to a CCU and 3150 (61.8%) to a ward, and this varied by region: 50.6% AP, 63.3% CE, 60.7% WE, 22.1% LA, and 28.6% NA. The 30-day death or readmission rate was 15.2% in ward patients and 17.0% in CCU patients (risk-adjusted Odds Ratio [OR] 1.44: 95% CI, 1.14–1.82). Compared with CCU patients in NA (24.1% 30-day event rate), the primary outcomes were: AP (10.4%, Odds Ratio [OR] 0.63; 95% confidence Interval [CI], 0.35 to 1.15), CE (10.4%, OR 0.56: 95% CI, 0.31 to 1.02), LA (22.4%, OR 0.60: 95% CI, 0.11 to 3.32), and WE (11.2%, OR 0.63, 95% CI, 0.25 to 1.56). No regional differences in 30-day mortality were observed; however, 30-day readmission rates were highest in NA sites. Conclusions: Management of patients with ADHF varies significantly, and after adjustment, CCU care was associated with higher risk of early mortality, not explained by international differences. These findings may help to improve the early decisions regarding risk stratification of patients hospitalized with ADHF. [ABSTRACT FROM AUTHOR]

Objective: Dietary strategies in heart failure (HF) are focused on sodium and fluid restriction to minimize the risk for acute volume overload episodes. However, the importance of dietary factors beyond sodium intake in the prognosis of the disease is uncertain. The purpose of this study was to evaluate the association of macro- and micronutrients intake on 1-y mortality in patients with HF. Methods: A secondary analysis of 203 patients with chronic HF enrolled in a randomized trial of sodium reduction was completed. Patients with a complete 3-d food record at baseline were included in this analysis (N = 118); both control and intervention arms were combined. Three-d mean dietary intake was estimated. Cox multivariable regression analysis was used to evaluate the association between dietary factors and 1-y mortality. Results: Among the 118 included patients, 54% were men, median (25th-75th percentiles) age 66 y (52-75 y), median ejection fraction 45% (30%-60%), and ischemic etiology present in 49% of patients. The association with 1-y mortality was significant for both polyunsaturated fatty acids (PUFA; adjusted hazard ratio [HR], 0.67; 95% confidence interval [CI]. 0.51-0.86 for intake as percentage of daily energy) and saturated fatty acids (SFA; adjusted HR, 1.15; 95% CI, 1.03-1.30 for intake as percentage of daily energy). Median of intake as percentage of daily energy was 5.3% for PUFAs and 8.2% for SFAs. Conclusions: Intake of PUFAs and SFAs was independently associated with 1 -y all-cause mortality in patients with chronic HF. Limiting dietary SFA and increasing PUFA intake may be advisable in this population. [ABSTRACT FROM AUTHOR]

Background We evaluated the prespecified endpoint, aborted myocardial infarction (AbMI), according to the use of a pharmacoinvasive (PI) strategy versus primary percutaneous coronary intervention (PCI) in 1754 patients randomised within 3 h of symptom onset in the STrategic Reperfusion Early After Myocardial infarction (STREAM) trial. Methods Based on sequential ECG's and biomarkers, AbMI was defined as ST-elevation resolution =50% (90 min posttenecteplase (TNK) in the PI arm or 30 min postprimary PCI) with minimal biomarker rise. Results In the PI arm 11.1% (n=99) had AbMI versus 6.9% (n=59) in primary PCI arm ( p<0.01). In a multivariable model, AbMI patients overall had less baseline SST-deviation, fewer baseline Q-waves and shorter total ischaemic times. PI AbMI patients had faster time to TNK (90 vs 100 min, p=0.015): total ischaemic time was 100 min longer in primary PCI AbMI patients and no difference in ischaemic time existed between AbMI and non-AbMI patients within this group. Although no significant interaction between treatment and AbMI on the composite endpoint of death/shock/congestive heart failure/recurrent MI occurred (p=0.292), PI AbMI patients had a lower incidence in this endpoint than non- AbMI patients (5.1 vs 12%, p=0.038); this was not evident in primary PCI patients. Forty-five patients (ie, 2.5%) had masquerading MI with minimal biomarker elevation and no evolution in baseline ST-elevation. Conclusions A PI strategy of early fibrinolysis more frequently aborts MI than primary PCI. Such PI patients had more favourable outcomes as compared with non- AbMIs. Diligent review of ECG evolution in STEMI distinguishes AbMI from infarct masquerade. Clinical Trials.gov ID NCT00623623. [ABSTRACT FROM AUTHOR]

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 < 0.001). Complete ST-segment resolution was greatest and all-cause mortality lowest among those with symptom onset three hours or less before percutaneous coronary intervention and no baseline Q waves. After multivariable adjustment, baseline Q waves, but not time from symptom onset, were associated with a significant increase in all-cause mortality (adjusted HR 1.42, 95% CI 1.10-2.01, 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. [ABSTRACT FROM AUTHOR]