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Background Despite oral anticoagulation, patients with atrial fibrillation (AF) remain at risk of ischemic stroke and systemic embolism (SE) events. For patients whose residual risk is sufficiently high, additional therapies might be useful to mitigate stroke risk. Methods and Results Individual patient data from 5 landmark trials testing oral anticoagulation in AF were pooled in A Collaboration Between Multiple Institutions to Better Investigate Non‐Vitamin K Antagonist Oral Anticoagulant Use in AF (COMBINE AF). We calculated the rate of ischemic stroke/SE among oral anticoagulation–treated patients with a CHA2DS2‐VASc score≥2, across strata of CHA2DS2‐VASc score, stroke history, and AF type, as either paroxysmal or nonparoxysmal. We included 71 794 patients with AF (median age 72 years, interquartile range, 13 years, 61.3% male) randomized to a direct oral anticoagulant or vitamin K antagonist, and followed for a mean of 2.1 (±0.8) years. The median CHA2DS2‐VASc score was 4 (interquartile range, 3–5), 18.8% had a prior stroke, and 76.4% had nonparoxysmal AF. The overall rate of stroke/SE was 1.33%/y (95% CI, 1.27–1.39); 1.38%/y (95% CI, 1.31–1.45) for nonparoxysmal AF, and 1.15%/y (95% CI, 1.05–1.27) for paroxysmal AF. The rate of ischemic stroke/SE increased by a rate ratio of 1.36 (95% CI, 1.32–1.41) per 1‐point increase in CHA2DS2‐VASc, reaching 1.67%/y (95% CI, 1.59–1.75) ≥4 CHA2DS2‐VASc points. Patients with both nonparoxysmal AF and CHA2DS2‐VASc ≥4 had a stroke/SE rate of 1.75%/y (95% CI, 1.66–1.85). In patients with a prior stroke, the risk was 2.51%/y (95% CI, 2.33–2.71). Conclusions AF type, CHA2DS2‐VASc score, and stroke history can identify patients with AF, who despite oral anticoagulation have a residual stroke/SE risk of 1.5% to 2.5% per year. Evaluation of additional stroke/SE prevention strategies in high‐risk patients is warranted.

Background: Little is known regarding the characteristics, treatment patterns, and outcomes in patients with adult congenital heart disease (ACHD) admitted to cardiac intensive care units (CICUs). Objectives: The authors sought to better define the contemporary epidemiology, treatment patterns, and outcomes of ACHD admissions in the CICU. Methods: The Critical Care Cardiology Trials Network is a multicenter network of CICUs in North America. Participating centers contributed prospective data from consecutive admissions during 2-month annual snapshots from 2017 to 2022. We analyzed characteristics and outcomes of admissions with ACHD compared with those without ACHD. Multivariable logistic regression was used to assess mortality in ACHD vs non-ACHD admissions. Results: Of 23,299 CICU admissions across 42 sites, there were 441 (1.9%) ACHD admissions. Shunt lesions were most common (46.1%), followed by right-sided lesions (29.5%) and complex lesions (28.7%). ACHD admissions were younger (median age 46 vs 67 years) than non-ACHD admissions. ACHD admissions were more commonly for heart failure (21.3% vs 15.7%, P

Background BMP10 (bone morphogenic protein 10) has emerged as a novel biomarker associated with the risk of ischemic stroke and other outcomes in patients with atrial fibrillation (AF). The study aimed to determine if repeated BMP10 measurements improve prognostication of cardiovascular events in patients with AF. Methods and Results BMP10 was measured using a prototype Elecsys immunoassay in plasma samples collected at randomization and after 2 months in patients with AF randomized to apixaban or warfarin in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial (n=2878). Adjusted Cox‐regression models were used to evaluate the association between 2‐month BMP10 levels and outcomes. BMP10 levels increased by 7.8% (P

Background: Registry-based trials have the potential to reduce randomized clinical trial (RCT) costs. However, observed cost differences also may be achieved through pragmatic trial designs. A systematic comparison of trial costs across different designs has not been previously performed. Methods: We conducted a study to compare the current Steroids to Reduce Systemic inflammation after infant heart surgery (STRESS) registry-based RCT vs. two established designs: pragmatic RCT and explanatory RCT. The primary outcome was total RCT design costs. Secondary outcomes included: RCT duration and personnel hours. Costs were estimated using the Duke Clinical Research Institute's pricing model. Results: The Registry-Based RCT estimated duration was 31.9 weeks greater than the other designs (259.5 vs. 227.6 weeks). This delay was caused by the Registry-Based design's periodic data harvesting that delayed site closing and statistical reporting. Total personnel hours were greatest for the Explanatory design followed by the Pragmatic design and the Registry-Based design (52,488 vs 29,763 vs. 24,480 h, respectively). Total costs were greatest for the Explanatory design followed by the Pragmatic design and the Registry-Based design ($10,140,263 vs. $4,164,863 vs. $3,268,504, respectively). Thus, Registry-Based total costs were 32 % of the Explanatory and 78 % of the Pragmatic design. Conclusion: Total costs for the STRESS RCT with a registry-based design were less than those for a pragmatic design and much less than an explanatory design. Cost savings reflect design elements and leveraging of registry resources to improve cost efficiency, but delays to trial completion should be considered.

Aim of the study: Survival to hospital discharge from out-of-hospital cardiac arrest (OHCA) after receiving treatment from emergency medical services (EMS) is less than 10% in the United States. Community-focused interventions improve survival rates, but there is limited information on how to gain support for new interventions or program activities within these populations. Using data from the RAndomized Cluster Evaluation of Cardiac ARrest Systems (RACE-CARS) trial, we aimed to identify the factors influencing emergency response agencies’ support in implementing an OHCA intervention. Methods: North Carolina counties were stratified into high-performing or low-performing counties based on the county’s cardiac arrest volume, percent of bystander-cardiopulmonary resuscitation (CPR) performed, patient survival to hospital discharge, cerebral performance in patients after cardiac arrest, and perceived engagement in the RACE-CARS project. We randomly selected 4 high-performing and 3 low-performing counties and conducted semi-structured qualitative interviews with emergency response stakeholders in each county. Results: From 10/2021 to 02/2022, we completed 29 interviews across the 7 counties (EMS (n = 9), telecommunications (n = 7), fire/first responders (n = 7), and hospital representatives (n = 6)). We identified three themes salient to community support for OHCA intervention: (1) initiating support at emergency response agencies; (2) obtaining support from emergency response agency staff (senior leadership and emergency response teams); and (3) and maintaining support. For each theme, we described similarities and differences by high- and low-performing county. Conclusions: We identified techniques for supporting effective engagement of emergency response agencies in community-based interventions for OHCA improving survival rates. This work may inform future programs and initiatives around implementation of community-based interventions for OHCA.

Background Studies demonstrated sex differences in outcomes following acute myocardial infarction, with women more likely to develop heart failure (HF). Sacubitril/valsartan has been shown to reduce cardiovascular death and HF hospitalizations in patients with HF with reduced ejection fraction. Methods and Results A total of 5661 patients (1363 women [24%]) with acute myocardial infarction complicated by reduced left ventricular ejection fraction (≤40%), pulmonary congestion, or both and ≥1 of 8 risk‐augmenting factors were randomized to receive sacubitril/valsartan or ramipril. The primary outcome was cardiovascular death or incident HF. Baseline characteristics, clinical outcomes, and safety events were compared according to sex, a prespecified subgroup. Female participants were older and had more comorbidities. After multivariable adjustment, women and men were at similar risks for cardiovascular death or all‐cause death. Women were more likely to have first HF hospitalization (hazard ratio [HR], 1.34 [95% CI, 1.05–1.70]; P=0.02) and total HF hospitalizations (HR, 1.39 [95% CI, 1.05–1.84]; P=0.02). Sex did not significantly modify the treatment effect of sacubitril/valsartan compared with ramipril on the primary outcome (P for interaction=0.11). Conclusions In contemporary patients who presented with reduced left ventricular ejection fraction, pulmonary congestion, or both, following acute myocardial infarction, women had a higher incidence of HF during follow‐up. Sex did not modify the treatment effect of sacubitril/valsartan relative to ramipril. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02924727.

Apixaban is a direct oral anticoagulant, a factor Xa inhibitor, used for the prevention of ischemic stroke in patients with atrial fibrillation. Despite using recommended dosing a few patients might still experience bleeding or lack of efficacy that might be related to inappropriate drug exposure. We conducted a genome-wide association study using data from 1,325 participants in the pivotal phase three trial of apixaban with the aim to identify genetic factors affecting the pharmacokinetics of apixaban. A candidate gene analysis was also performed for pre-specified variants in ABCB1, ABCG2, CYP3A4, CYP3A5, and SULT1A1, with a subsequent analysis of all available polymorphisms within the candidate genes. Significant findings were further evaluated to assess a potential association with clinical outcome such as bleeding or thromboembolic events. No variant was consistently associated with an altered apixaban exposure on a genome-wide level. The candidate gene analyses showed a statistically significant association with a well-known variant in the drug transporter gene ABCG2 (c.421G > T, rs2231142). Patients carrying this variant had a higher exposure to apixaban [area under the curve (AUC), beta = 151 (95% CI 59–243), p = 0.001]. On average, heterozygotes displayed a 5% increase of AUC and homozygotes a 17% increase of AUC, compared with homozygotes for the wild-type allele. Bleeding or thromboembolic events were not significantly associated with ABCG2 rs2231142. This large genome-wide study demonstrates that genetic variation in the drug transporter gene ABCG2 is associated with the pharmacokinetics of apixaban. However, the influence of this finding on drug exposure was small, and further studies are needed to better understand whether it is of relevance for ischemic and bleeding events.

Background We sought to determine recurrent stroke predictors among patients with embolic strokes of undetermined source (ESUS). Methods and Results We applied Cox proportional hazards models to identify clinical features associated with recurrent stroke among participants enrolled in RE‐SPECT ESUS (Randomized, Double‐Blind, Evaluation in Secondary Stroke Prevention Comparing the Efficacy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate Versus Acetylsalicylic Acid in Patients With Embolic Stroke of Undetermined Source) trial, an international clinical trial evaluating dabigatran versus aspirin for patients with ESUS. During a median follow‐up of 19 months, 384 of 5390 participants had recurrent stroke (annual rate, 4.5%). Multivariable models revealed that stroke or transient ischemic attack before the index event (hazard ratio [HR], 2.27 [95% CI, 1.83–2.82]), creatinine clearance

Background Following the implementation of the HeartRescue project, with interventions in the community, emergency medical services, and hospitals to improve care and outcomes for out‐of‐hospital cardiac arrests (OHCA) in North Carolina, improved bystander and first responder treatments as well as survival were observed. This study aimed to determine whether these improvements were consistent across Black versus White individuals. Methods and Results Using the Cardiac Arrest Registry to Enhance Survival (CARES), we identified OHCA from 16 counties in North Carolina (population 3 million) from 2010 to 2014. Temporal changes in interventions and outcomes were assessed using multilevel multivariable logistic regression, adjusted for patient and socioeconomic neighborhood‐level factors. Of 7091 patients with OHCA, 36.5% were Black and 63.5% were White. Black patients were younger, more females, had more unwitnessed arrests and non‐shockable rhythm (Black: 81.0%; White: 75.4%). From 2010 to 2014, the adjusted probabilities of bystander cardiopulmonary resuscitation (CPR) went from 38.5% to 51.2% in White, P

Background Evidence‐based therapies are generally underused for cardiovascular risk reduction; however, less is known about contemporary patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease. Methods and Results Pharmacy and medical claims data from within Anthem were queried for patients with established atherosclerotic cardiovascular disease and type 2 diabetes mellitus. Using an index date of April 18, 2018, we evaluated the proportion of patients with a prescription claim for any of the 3 evidence‐based therapies on, or covering, the index date ±30 days: high‐intensity statin, angiotensin‐converting enzyme inhibitor or angiotensin receptor blocker, and sodium glucose cotransporter‐2 inhibitor or glucagon‐like peptide‐1 receptor agonist. The potential benefit of achieving 100% adoption of all 3 evidence‐based therapies was simulated using pooled treatment estimates from clinical trials. Of the 155 958 patients in the sample, 24.7% were using a high‐intensity statin, 53.1% were using an angiotensin‐converting enzyme inhibitor or angiotensin receptor blocker, and 9.9% were using either an sodium glucose cotransporter‐2 inhibitor or glucagon‐like peptide‐1 receptor agonists. Overall, only 2.7% of the population were covered by prescriptions for all 3 evidence‐based therapies, and 37.4% were on none of them. Over a 12‐month period, 70.6% of patients saw a cardiologist, while only 18% saw an endocrinologist. Increasing the use of evidence‐based therapies to 100% over 3 years of treatment could be expected to reduce 4546 major atherosclerotic cardiovascular events (myocardial infarction, stroke, or cardiovascular death) in eligible but untreated patients. Conclusions Alarming gaps exist in the contemporary use of evidence‐based therapies in this large population of insured patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease. These data provide a call to action for patients, providers, industry, regulators, professional societies, and payers to close these gaps in care.

Background To explore the pathophysiological features of ischemic stroke in patients with atrial fibrillation (AF), we evaluated the association between 268 plasma proteins and subsequent ischemic stroke in 2 large AF cohorts receiving oral anticoagulation. Methods and Results A case‐cohort sample of patients with AF from the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, including 282 cases with ischemic stroke or systemic embolism and a random sample of 4124 without these events, during 1.9 years of follow‐up was used for identification. Validation was provided by a similar case‐cohort sample of patients with AF from the RE‐LY (Randomized Evaluation of Long‐Term Anticoagulation Therapy) trial, including 149 cases with ischemic stroke/systemic embolism and a random sample of 1062 without these events. In plasma obtained before randomization, 268 unique biomarkers were measured with OLINK proximity extension assay panels (CVD II, CVD III, and Inflammation) and conventional immunoassays. The association between biomarkers and outcomes was evaluated by random survival forest and adjusted Cox regression. According to random survival forest or Cox regression analyses, the biomarkers most strongly and consistently associated with ischemic stroke/systemic embolism were matrix metalloproteinase‐9, NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), osteopontin, sortilin, soluble suppression of tumorigenesis 2, and trefoil factor‐3. The corresponding hazard ratios (95% CIs) for an interquartile difference were as follows: 1.18 (1.00–1.38), 1.55 (1.28–1.88), 1.28 (1.07–1.53), 1.19 (1.02–1.39), 1.23 (1.05–1.45), and 1.19 (0.97–1.45), respectively. Conclusions In patients with AF, of 268 unique biomarkers, the 6 biomarkers most strongly associated with subsequent ischemic stroke/systemic embolism represent fibrosis/remodeling (matrix metalloproteinase‐9 and soluble suppression of tumorigenesis 2), cardiac dysfunction (NT‐proBNP), vascular calcification (osteopontin), metabolism (sortilin), and mucosal integrity/ischemia (trefoil factor‐3). Registration URL: https://www.clinicaltrials.gov. Unique Identifiers: NCT00412984 and NCT00262600.

Background Knowledge is scarce regarding how multimorbidity is associated with therapeutic decisions regarding oral anticoagulants (OACs) in patients with atrial fibrillation. Methods and Results We conducted a cross‐sectional study of hospitalized patients with atrial fibrillation using the Get With The Guidelines‐Atrial Fibrillation registry from 2013 to 2019. We identified patients ≥65 years and eligible for OAC therapy. Using 16 available comorbidity categories, patients were stratified by morbidity burden. A multivariable logistic regression model was used to determine the odds of receiving OAC prescription at discharge by morbidity burden. We included 34 174 patients with a median (interquartile range) age of 76 (71–83) years, 56.6% women, and 41.9% were not anticoagulated at admission. Of these patients, 38.6% had 0 to 2 comorbidities, 50.7% had 3 to 5 comorbidities, and 10.7% had ≥6 comorbidities. The overall discharge OAC prescription was high (85.6%). The prevalence of patients with multimorbidity increased from 59.7% in 2014 to 64.3% in 2019 (P trend=0.002). Using 0 to 2 comorbidities as the reference, the adjusted odds ratio (95% CI) of OAC prescription were 0.93 (0.82, 1.05) for patients with 3 to 5 comorbidities and 0.72 (0.60, 0.86) for patients with ≥6 comorbidities. In those with ≥6 comorbidities, the most common reason for nonprescription of OACs were frequent falls/frailty (31.0%). Conclusions In a contemporary quality‐of‐care database of hospitalized patients with atrial fibrillation eligible for OAC therapy, multimorbidity was common. A higher morbidity burden was associated with a lower odds of OAC prescription. This highlights the need for interventions to improve adherence to guideline‐recommended anticoagulation in multimorbid patients with atrial fibrillation.

Background We compared different methods of estimated glomerular filtration rate (eGFR) and their association with cardiovascular death and major bleeding in 14 980 patients with atrial fibrillation in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial. Methods and Results eGFR was calculated using equations based on creatinine (Cockcroft‐Gault, Modification of Diet in Renal Disease, and Chronic Kidney Disease Epidemiology Collaboration [CKD‐EPI]) and/or cystatin C (CKD‐EPICysC and CKD‐EPICysC+Creatinine). These 5 eGFR equations, as well as the individual variables that are used in these equations, were assessed for correlation and discriminatory ability for cardiovascular death and major bleeding. The median age was 70.0 years, and 35.6% were women. The median eGFR was highest with Cockcroft‐Gault (74.1 mL/min) and CKD‐EPICysC (74.2 mL/min), and lowest with Modification of Diet in Renal Disease (66.5 mL/min). Correlation between methods ranged from 0.49 (Cockroft‐Gault and CKD‐EPICysC) to 0.99 (Modification of Diet in Renal Disease and CKD‐EPI). Among the eGFR equations, those based on cystatin C yielded the highest C indices for cardiovascular death and major bleeding: 0.628 (CKD‐EPICysC) and 0.612 (CKD‐EPICysC+Creatinine), respectively. A model based on the variables within the different eGFR equations (age, sex, weight, creatinine, and cystatin C) yielded the highest discriminatory value for both outcomes, with a C index of 0.673 and 0.656, respectively. Conclusions In patients with atrial fibrillation on anticoagulation, correlation between eGFR calculated using different methods varied substantially. Cystatin C–based eGFRs seem to provide the most robust information for predicting death and bleeding. A model based on the individual variables within the eGFR equations, however, provided the highest discriminatory value. Our findings may help refine risk stratification in patients with atrial fibrillation and define how renal function should be determined in future atrial fibrillation studies. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT00412984.

Background Despite restoration of epicardial flow following primary percutaneous coronary intervention (PPCI), microvascular reperfusion as reflected by ST‐elevation resolution (ST‐ER) resolution remains variable and its pathophysiology remains unclear. Methods and Results Using principal component analyses, we explored associations between 91 serum biomarkers drawn before PPCI clustered into 14 pathobiologic processes (including NT‐proBNP [N‐terminal pro‐B‐type natriuretic peptide] as an independent cluster), and (1) ST‐ER resolution ≥50% versus

Background Identification of patients with stable coronary heart disease who are at significant residual risk could be helpful for targeted prevention. Our aim was to determine the prognostic value of the recently introduced ceramide‐ and phospholipid‐based risk score, the Cardiovascular Event Risk Test (CERT2), in patients with stable coronary heart disease on optimal medical therapy and to identify biological processes that contribute to the CERT2 score. Methods and Results Plasma samples (n=11 222) obtained from the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial were analyzed using a tandem liquid chromatography‐mass spectrometry method. STABILITY was a trial in patients with stable coronary heart disease randomized to the lipoprotein‐associated phospholipase A2 inhibitor darapladib or placebo on optimized medical therapy at baseline, with a median follow‐up of 3.7 years. Hazard ratios per SD for the CERT2 risk score were 1.32 (95% CI, 1.25–1.39) for major adverse cardiovascular event, 1.47 (95% CI, 1.35–1.59) for cardiovascular death, 1.32 (95% CI, 1.16–1.49) for stroke, 1.23 (95% CI, 1.14–1.33) for myocardial infarction, and 1.56 (95% CI, 1.39–1.76) for hospitalization due to heart failure, when adjusted for traditional cardiovascular risk factors. CERT2 showed correlation (P0.2) with inflammatory markers high‐sensitivity C‐reactive protein, interleukin 6, the heart failure marker N‐terminal pro‐B‐type natriuretic peptide, and low‐density lipoprotein cholesterol. After also adjusting for levels of other prognostic biomarkers, the CERT2 score was still independently related to the risk of cardiovascular death but not to nonfatal events. Conclusions The CERT2 risk score can detect residual risk in patients with stable coronary heart disease and is associated with biomarkers indicating inflammation, myocardial necrosis, myocardial dysfunction, renal dysfunction, and dyslipidemia. REGISTRATION URL: https://www.clini​caltr​ials.gov. Unique identifier: NCT00799903.

OBJECTIVES/GOALS: We sought to examine: 1) variability in center acceptance patterns for heart allografts offered to the highest-priority candidates, 2) impact of this acceptance behavior on candidate survival, and 3) post-transplantation outcomes in candidates who accepted first rank offer vs. previously declined offer. METHODS/STUDY POPULATION: In this retrospective cohort study, the US national transplant registry was queried for all match runs of adult candidates listed for isolated heart transplantation between 2007-2017. We examined center acceptance rates for heart allografts offered to the highest-priority candidates and accounted for covariates in multivariable logistic regression. Competing risks analysis was performed to assess the relationship between center acceptance rate and waitlist mortality. Post-transplantation outcomes (patient survival and graft failure) between candidates who accepted their first-rank offers vs those who accepted previously declined offers were compared using Fine-Gray subdistribution hazards model. RESULTS/ANTICIPATED RESULTS: Among 19,703 unique organ offers, 6,302 (32%) were accepted for first-ranked candidates. After adjustment for donor, recipient, and geographic covariates, transplant centers varied markedly in acceptance rates (12%-62%) of offers made to first-ranked candidates. Lowest acceptance rate centers (

Background We aimed to determine the change in treatment strategies and times to treatment over the first 5 years of the Mission: Lifeline program. Methods and Results We assessed pre‐ and in‐hospital care and outcomes from 2008 to 2012 for patients with ST‐segment–elevation myocardial infarction at US hospitals, using data from the National Cardiovascular Data Registry Acute Coronary Treatment and Intervention Outcomes Network Registry—Get With The Guidelines Registry. In‐hospital adjusted mortality was calculated including and excluding cardiac arrest as a reason for primary percutaneous coronary intervention delay. A total of 147 466 patients from 485 hospitals were analyzed. There was a decrease in the proportion of eligible patients not treated with reperfusion (6.2% versus 3.3%) and treated with fibrinolytic therapy (13.4% versus 7.0%). Median time from symptom onset to first medical contact was unchanged (≈50 minutes). Use of prehospital ECGs increased (45% versus 71%). All major reperfusion times improved: median first medical contact‐to‐device for emergency medical systems transport to percutaneous coronary intervention–capable hospitals (93 to 84 minutes), first door‐to‐device for transfers for primary percutaneous coronary intervention (130 to 112 minutes), and door‐in–door‐out at non–percutaneous coronary intervention–capable hospitals (76 to 62 minutes) (all P

Background Firefighter first responders dispatched in parallel with emergency medical services (EMS) personnel for out‐of‐hospital cardiac arrests (OHCA) can provide early defibrillation to improve survival. We examined whether survival following first responder defibrillation differed according to driving distance from nearest fire station to OHCA site. Methods and Results From the CARES (Cardiac Arrest Registry to Enhance Survival) registry, we identified non‐EMS witnessed OHCAs of presumed cardiac cause from 2010 to 2014 in Durham, Mecklenburg, and Wake counties, North Carolina. We used logistic regression to estimate the association between calculated driving distances (≤1, 1–1.5, 1.5–2, and >2 miles) and survival to hospital discharge following first responder defibrillation compared with defibrillation by EMS personnel. In total, 5020 OHCAs were included in the study. First responders more often applied the first automated external defibrillators at the shortest distances (≤1 mile) versus longest distances (>2 miles) (53.4% versus 46.6%, respectively, P2.0 miles), survival following first responder defibrillation did not differ from EMS defibrillation (odds ratio 0.77 [95% confidence interval 0.48–1.21] and odds ratio 0.97 [95% confidence interval 0.67–1.41], respectively). Conclusions Shorter driving distance from nearest fire station to OHCA location was associated with improved survival following defibrillation by first responders. These results suggest that the location of first responder units should be considered when organizing prehospital systems of OHCA care.

Background: Little is known about clinical outcomes of patients with acute myocardial infraction (AMI) complicated by cardiogenic shock (CS) requiring mechanical ventilation (MV). The aim of this study was to identify the characteristics, risk factors, and outcomes associated with the provision of MV in this specific high-risk population. Methods: Patients with CS complicating AMI and multivessel coronary artery disease from the CULPRIT-SHOCK trial were included. We explored 30 days of clinical outcomes in patients not requiring MV, those with MV on admission, and those in whom MV was initiated within the first day after admission. Results: Among 683 randomized patients included in the analysis, 17.4% received no MV, 59.7% were ventilated at admission and 22.8% received MV within or after the first day after admission. Patients requiring MV had a different risk-profile. Factors independently associated with the provision of MV on admission included higher body weight, resuscitation within 24 h before admission, elevated heart rate and evidence of triple vessel disease. Conclusions: Requiring MV in patients with CS complicating AMI is common and independently associated with mortality after adjusting for covariates. Patients with delayed MV initiation appear to be at higher risk of adverse outcomes. Further research is necessary to identify the optimal timing of MV in this high-risk population.

Background The Institute of Medicine has called for actions to understand and target sex‐related differences in care and outcomes for out‐of‐hospital cardiac arrest patients. We assessed changes in bystander and first‐responder interventions and outcomes for males versus females after statewide efforts to improve cardiac arrest care. Methods and Results We identified out‐of‐hospital cardiac arrests from North Carolina (2010–2014) through the CARES (Cardiac Arrest Registry to Enhance Survival) registry. Outcomes for men versus women were examined through multivariable logistic regression analyses adjusted for (1) nonmodifiable factors (age, witnessed status, and initial heart rhythm) and (2) nonmodifiable plus modifiable factors (bystander cardiopulmonary resuscitation and defibrillation before emergency medical services), including interactions between sex and time (ie, year and year2). Of 8100 patients, 38.1% were women. From 2010 to 2014, there was an increase in bystander cardiopulmonary resuscitation (men, 40.5%–50.6%; women, 35.3%–51.8%; P for each

Background Few data exist on regional systems of care for the treatment of ST‐segment–elevation myocardial infarction (STEMI) in developing countries. Our objective was to describe temporal trends in 30‐day mortality and identify predictors of mortality among STEMI patients enrolled in a prospective registry in Brazil. Methods and Results From January 2011 to June 2013, 520 patients who received initial STEMI care at 23 nonspecialized public health units or hospitals, some of whom were transferred to a public cardiology referral center, were identified through a regional STEMI network supported by telemedicine and the local prehospital emergency medical service. We stratified patients into five 6‐month periods based on presentation date. Mean age (±SD) of patients was 62.0 (±12.2) years, and 55.6% were men. The mean Global Registry of Acute Coronary Events (GRACE) score was 145 (±34). Overall mortality at 30 days was 15.0%. Use of dual antiplatelet therapy and statins increased significantly from baseline (January 2011) to period 5 (June 2013): 61.8% to 93.6% (P

BackgroundDyslipidemia is a major risk factor for cardiovascular events. The prognostic importance of lipoproteins in patients with atrial fibrillation is not well understood. We aimed to explore the association between apolipoprotein A1 (ApoA1) and B (ApoB) and cardiovascular events in patients with atrial fibrillation receiving oral anticoagulation. Methods and ResultsUsing data from the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, ApoA1 and ApoB plasma levels were measured at baseline in 14 884 atrial fibrillation patients. Median length of follow‐up was 1.9 years. Relationships between continuous levels of ApoA1 and ApoB and clinical outcomes were evaluated using Cox models adjusted for cardiovascular risk factors, medication including statins, and cardiovascular biomarkers. A composite ischemic outcome (ischemic stroke, systemic embolism, myocardial infarction, and cardiovascular death) was used as the primary end point. Median (25th, 75th) ApoA1 and ApoB levels were 1.10 (0.93, 1.30) and 0.70 g/L (0.55, 0.85), respectively. In adjusted analyses, higher levels of ApoA1 were independently associated with a lower risk of the composite ischemic outcome (hazard ratio, 0.81; P

BackgroundCardiac biomarkers are independent risk markers in atrial fibrillation, and the novel biomarker–based ABC stroke score (age, biomarkers, and clinical history of prior stroke) was recently shown to improve the prediction of stroke risk in patients with atrial fibrillation. Our aim was to investigate the short‐term variability of the cardiac biomarkers and evaluate whether the ABC stroke risk score provides a stable short‐term risk estimate. Methods and ResultsAccording to the study protocol, samples were obtained at entry and also at 2 months in 4796 patients with atrial fibrillation followed for a median of 1.8 years in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial. Cardiac troponin I, cardiac troponin T, and N‐terminal pro‐B‐type natriuretic peptide were measured with high‐sensitivity immunoassays. Associations with outcomes were evaluated by Cox regression. C indices and calibration plots were used to evaluate the ABC stroke score at 2 months. The average changes in biomarker levels during 2 months were small (median change cardiac troponin T +2.8%, troponin I +2.0%, and N‐terminal pro‐B‐type natriuretic peptide +13.5%) and within‐subject correlation was high (all ≥0.82). Repeated measurement of cardiac biomarkers provided some incremental prognostic value for mortality but not for stroke when combined with clinical risk factors and baseline levels of the biomarkers. Based on 8702 person‐years of follow‐up and 96 stroke/systemic embolic events, the ABC stroke score at 2 months achieved a similar C index of 0.70 (95% CI, 0.65–0.76) as compared with 0.70 (95% CI, 0.65–0.75) at baseline. The ABC stroke score remained well calibrated using predefined risk classes. ConclusionsIn patients with stable atrial fibrillation, the variability of the cardiac biomarkers and the biomarker‐based ABC stroke score during 2 months are small. The prognostic information by the ABC stroke score remains consistent and well calibrated with similar good predictive performance if patients are retested after 2 months. Clinical Trial RegistrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT00412984.

BackgroundPrior Studies have suggested better outcomes in smokers compared with nonsmokers receiving clopidogrel (“smoker's paradox”). The impact of a more intensive clopidogrel regimen on ischemic and bleeding risks in smokers with acute coronary syndromes requiring percutaneous coronary interventions remains unclear. Methods and ResultsWe analyzed 17 263 acute coronary syndrome patients undergoing percutaneous coronary intervention from the CURRENT‐OASIS 7 (Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events—Seventh Organization to Assess Strategies in Ischemic Symptoms) trial, which compared double‐dose (600 mg day 1;150 mg days 2–7; then 75 mg daily) versus standard‐dose (300 mg day 1; then 75 mg daily) clopidogrel in acute coronary syndrome patients. The primary outcome was cardiovascular death, myocardial infarction, or stroke at 30 days. Interactions between treatment allocation and smoking status (current smokers versus nonsmokers) were evaluated. Overall, 6394 patients (37.0%) were current smokers. For the comparison of double‐ versus standard‐dose clopidogrel, there were significant interactions in smokers and nonsmokers for the primary outcome (P=0.031) and major bleeding (P=0.002). Double‐ versus standard‐dose clopidogrel reduced the primary outcome among smokers by 34% (hazard ratio [HR] 0.66, 95% confidence interval [CI], 0.50–0.87, P=0.003), whereas in nonsmokers, there was no apparent benefit (HR 0.96, 95% CI, 0.80–1.14, P=0.61). For major bleeding, there was no difference between the groups in smokers (HR 0.77, 95% CI, 0.48–1.24, P=0.28), whereas in nonsmokers, the double‐dose clopidogrel regimen increased bleeding (HR 1.89, 95% CI, 1.37–2.60, P

BackgroundThe American Heart Association Mission: Lifeline STEMI (ST‐segment–elevation myocardial infarction) Systems Accelerator program, conducted in 16 regions across the United States to improve key care processes, resulted in more patients being treated within national guideline goals (time from first medical contact to device:

BackgroundPatients with ST‐elevation myocardial infarction (STEMI) with out‐of‐hospital cardiac arrest (OHCA) may benefit from direct transport to a percutaneous cardiac intervention (PCI) hospital but have previously been less likely to bypass local non‐PCI hospitals to go to a PCI center. Methods and ResultsWe reported time trends in emergency medical service transport and care of patients with STEMI with and without OHCA included from 171 PCI‐capable hospitals in 16 US regions with participation in the Mission: Lifeline STEMI Accelerator program between July 1, 2012, and March 31, 2014. Time trends by quarter were assessed using logistic regression with generalized estimating equations to account for hospital clustering. Of 13 189 emergency medical service–transported patients, 88.7% (N=11 703; 10.5% OHCA) were taken directly to PCI hospitals. Among 1486 transfer‐in patients, 21.7% had OHCA. Direct transport to a PCI center for OHCA increased from 74.7% (July 1, 2012) to 83.6% (March 31, 2014) (odds ratio per quarter, 1.07; 95% confidence interval, 1.02–1.14), versus 89.0% to 91.0% for patients without OHCA (odds ratio, 1.03; 95% confidence interval, 0.99–1.07; interaction P=0.23). The proportion with prehospital ECGs increased for patients taken directly to PCI centers (53.9%–61.9% for those with OHCA versus 73.9%–81.9% for those without OHCA; interaction P=0.12). Of 997 patients with OHCA taken directly to PCI hospitals and treated with primary PCI, first medical contact‐to‐device times within the guideline‐recommended goal of ≤90 minutes were met for 34.5% on July 1, 2012, versus 41.8% on March 31, 2014 (51.6% and 56.1%, respectively, for 9352 counterparts without OHCA; interaction P=0.72). ConclusionsDirect transport to PCI hospitals increased for patients with STEMI with and without OHCA during the 2012 to 2014 Mission: Lifeline STEMI Accelerator program. Proportions with prehospital ECGs and timely reperfusion increased for patients taken directly to PCI hospitals.

BackgroundThe HeartRescue Project is a multistate public health initiative focused on establishing statewide out‐of‐hospital cardiac arrest (OHCA) systems of care to improve case capture and OHCA care in the community, by emergency medical services (EMS), and at hospital level. Methods and ResultsFrom 2011 to 2015 in the 5 original HeartRescue states, all adults with EMS–treated OHCA due to a presumed cardiac cause were included. In an adult population of 32.8 million, a total of 64 988 OHCAs—including 10 046 patients with a bystander‐witnessed OHCA with a shockable rhythm—were treated by 330 EMS agencies. From 2011 to 2015, the case‐capture rate for all‐rhythm OHCA increased from an estimated 39.0% (n=6762) to 89.2% (n=16 103; P

BackgroundGreater understanding of differences between men and women with coronary heart disease is needed. Methods and ResultsIn this post hoc analysis of the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial, we described psychosocial factors, treatments, and outcomes of men versus women with stable coronary heart disease and explored the association of sex with psychosocial characteristics and cardiovascular risk. Cox proportional hazards models were used to assess the relationship between sex and outcomes. Interactions among sex, psychosocial factors, and the composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke were tested. Of 15 828 patients, 2967 (19%) were women. Among women, 21.2% felt often or always stressed at home (versus 9.8% of men), and 19.2% felt often or always sad or depressed (versus 10.1% of men; all P

BackgroundWe studied (1) the rates of stroke or systemic embolism and bleeding in patients with atrial fibrillation and peripheral artery disease (PAD) and (2) the efficacy and safety of apixaban versus warfarin in patients with atrial fibrillation with and without PAD. Methods and ResultsThe Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial randomized 18 201 patients with atrial fibrillation to apixaban or warfarin for stroke/systemic embolism prevention; 884 (4.9%) patients had PAD at baseline. Patients with PAD had higher unadjusted rates of stroke and systemic embolism (hazard ratio [HR] 1.73, 95% CI 1.22–2.45; P=0.002) and major bleeding (HR 1.34, 95% CI 1.00–1.81; P=0.05), but after adjustment, no differences existed in rates of stroke and systemic embolism (HR 1.32, 95% CI 0.93–1.88; P=0.12) and major bleeding (HR 1.03, 95% CI 0.76–1.40; P=0.83) compared with patients without PAD. The risk of stroke or systemic embolism was similar in patients assigned to apixaban and warfarin with PAD (HR 0.63, 95% CI 0.32–1.25) and without PAD (HR 0.80, 95% CI 0.66–0.96; interaction P=0.52). Patients with PAD did not have a statistically significant reduction in major or clinically relevant nonmajor bleeding with apixaban compared with warfarin (HR 1.05, 95% CI 0.69–1.58), whereas those without PAD had a statistically significant reduction (HR 0.65, 95% CI 0.58–0.73; interaction P=0.03). ConclusionsPatients with PAD in ARISTOTLE had a higher crude risk of stroke or systemic embolism compared with patients without PAD that was not present after adjustment. The benefits of apixaban versus warfarin for stroke and systemic embolism were similar in patients with and without PAD. These findings highlight the need to optimize the treatment of patients with atrial fibrillation and PAD. Clinical Trial RegistrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT00412984.

BackgroundWe evaluated lipoprotein‐associated phospholipase A2 (Lp‐PLA2) activity in patients with stable coronary heart disease before and during treatment with darapladib, a selective Lp‐PLA2 inhibitor, in relation to outcomes and the effects of darapladib in the STABILITY trial. Methods and ResultsPlasma Lp‐PLA2 activity was determined at baseline (n=14 500); at 1 month (n=13 709); serially (n=100) at 3, 6, and 18 months; and at the end of treatment. Adjusted Cox regression models evaluated associations between Lp‐PLA2 activity levels and outcomes. At baseline, the median Lp‐PLA2 level was 172.4 μmol/min per liter (interquartile range 143.1–204.2 μmol/min per liter). Comparing the highest and lowest Lp‐PLA2 quartile groups, the hazard ratios were 1.50 (95% CI 1.23–1.82) for the primary composite end point (cardiovascular death, myocardial infarction, or stroke), 1.95 (95% CI 1.29–2.93) for hospitalization for heart failure, 1.42 (1.07–1.89) for cardiovascular death, and 1.37 (1.03–1.81) for myocardial infarction after adjustment for baseline characteristics, standard laboratory variables, and other prognostic biomarkers. Treatment with darapladib led to a ≈65% persistent reduction in median Lp‐PLA2 activity. There were no associations between on‐treatment Lp‐PLA2 activity or changes of Lp‐PLA2 activity and outcomes, and there were no significant interactions between baseline and on‐treatment Lp‐PLA2 activity or changes in Lp‐PLA2 activity levels and the effects of darapladib on outcomes. ConclusionsAlthough high Lp‐PLA2 activity was associated with increased risk of cardiovascular events, pharmacological lowering of Lp‐PLA2 activity by ≈65% did not significantly reduce cardiovascular events in patients with stable coronary heart disease, regardless of the baseline level or the magnitude of change of Lp‐PLA2 activity. Clinical Trial RegistrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT00799903.

Background Patients with atrial fibrillation (AF) and hypertension are at high risk for stroke. Previous studies have shown elevated risk of stroke in patients with AF who have a history of hypertension (regardless of blood pressure [BP] control) and in patients with elevated BP. We assessed the association of hypertension and BP control on clinical outcomes. Methods and Results In ARISTOTLE (n=18 201), BP was evaluated as history of hypertension requiring treatment and elevated BP (systolic ≥140 and/or diastolic ≥90 mm Hg) at study entry and any point during the trial. Hazard ratios (HRs) were derived from Cox proportional hazards models including BP as a time‐dependent covariate. A total of 15 916 (87.5%) patients had a history of hypertension requiring treatment. In patients with elevated BP measurement at any point during the trial, the rate of stroke or systemic embolism was significantly higher (HR, 1.53; 95% confidence interval [CI], 1.25–1.86), as was hemorrhagic stroke (HR 1.85; 95% CI, 1.26–2.72) and ischemic stroke (HR, 1.50; 95% CI, 1.18–1.90). Rates of major bleeding were lower in patients with a history of hypertension (HR, 0.80; 95% CI, 0.66–0.98) and nonsignificantly lower in patients with elevated BP at study entry (HR, 0.89; 95% CI, 0.77–1.03). The benefit of apixaban versus warfarin on preventing stroke or systemic embolism was consistent among patients with and without a history of hypertension (P interaction=0.27), BP control at baseline (P interaction=0.43), and BP control during the trial (P interaction=0.97). Conclusions High BP measurement at any point during the trial was independently associated with a substantially higher risk of stroke or systemic embolism. These results strongly support efforts to treat elevated BP as an important strategy to optimally lower risk of stroke in patients with AF. Clinical Trial Registration URL: https://ClinicalTrials.gov/. Unique identifier: NCT00412984.

Atrial fibrillation is the most common arrhythmia and accounts for one-third of hospitalizations for rhythm disorders in the United States. The prevalence of atrial fibrillation averages 1% and increases with age. With the aging of the population, the number of patients with atrial fibrillation is expected to increase 150% by 2050, with more than 50% of atrial fibrillation patients being over the age of 80. This increasing burden of atrial fibrillation will lead to a higher incidence of stroke, as patients with atrial fibrillation have a five- to sevenfold greater risk of stroke than the general population. Strokes secondary to atrial fibrillation have a worse prognosis than in patients without atrial fibrillation. Vitamin K antagonists (e.g., warfarin), direct thrombin inhibitors (dabigatran), and factor Xa inhibitors (rivaroxaban and apixaban) are all oral anticoagulants that have been FDA approved for the prevention of stroke in atrial fibrillation. This review will summarize the experience of anticoagulants in patients with atrial fibrillation with a focus on the experience at the Duke Clinic Research Institute.