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OBJECTIVES: To compare the characteristics of Medicare beneficiaries hospitalized for heart failure (HF) and discharged home who received home healthcare (HHC) to those who did not, and to examine associations between HHC and readmission and mortality rates. BACKGROUND: After hospitalization for HF, some patients receive HHC; however, utilization of HHC over time, factors associated with its use and post-discharge outcomes after receiving it are not well studied. METHODS: We used Get With The Guidelines-HF data, merged with Medicare fee-for-service claims. Propensity-score matching and Cox proportional hazards models were used to evaluate the associations between HHC and post-discharge outcomes. RESULTS: From 2005 to 2015, 95,531 patients were admitted for HF and 32,697 (34.2%) received HHC after discharge. The rate of HHC increased over time from 31.4% to 36.1% (p

Objectives This study sought to determine the degree to which U.S. patients enrolled in a heart failure (HF) trial represent patients in routine U.S. clinical practice according to race and sex. Background Black patients and women are frequently under-represented in HF clinical trials. However, the degree to which black patients and women enrolled in trials represent such patients in routine practice is unclear. Methods The ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial randomized patients hospitalized for HF to receive nesiritide or placebo from May 2007 to August 2010 and was neutral for clinical endpoints. This analysis compared non-Hispanic white (n = 1,494) and black (n = 1,012) patients enrolled in ASCEND-HF from the U.S. versus non-Hispanic white and black patients included in a U.S. hospitalized HF registry (i.e., Get With The Guidelines–Heart Failure [GWTG-HF]) during the ASCEND-HF enrollment period and meeting trial eligibility criteria. Results Among 79,291 white and black registry patients, 49,063 (62%) met trial eligibility criteria (white, n = 37,883 [77.2%]; black, n = 11,180 [22.8%]). Women represented 35% and 49% of the ASCEND-HF and trial-eligible GWTG-HF cohorts, respectively. Compared with trial-enrolled patients, trial-eligible GWTG-HF patients tended to be older with higher blood pressure and higher ejection fraction. Trial-eligible patients had higher in-hospital mortality (2.3% vs. 1.3%), 30-day readmission (20.2% vs. 16.8%), and 180-day mortality (21.2% vs. 18.6%) than those enrolled in the trial (all p Conclusions Patients with HF seen in U.S. practice and eligible for the ASCEND-HF trial had worse clinical outcomes than those enrolled in the trial. After accounting for clinical characteristics, trial-eligible real-world patients continued to have higher rates of 30-day readmission, driven by differences among black patients and women. Social, behavioral, and other unmeasured factors may impair representativeness of patients enrolled in HF trials, particularly among racial/ethnic minorities and women. (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure [ASCEND-HF]; NCT00475852)

ObjectiveTo determine whether young adults (≤40 years old) with acute ischemic stroke are less likely to receive IV tissue plasminogen activator (tPA) and more likely to have longer times to brain imaging and treatment.MethodsWe analyzed data from the Get With The Guidelines–Stroke registry for patients with acute ischemic stroke hospitalized between January 2009 and September 2015. We used multivariable models with generalized estimating equations to evaluate tPA treatment and outcomes between younger (age 18–40 years) and older (age >40 years) patients with acute ischemic stroke.ResultsOf 1,320,965 patients with acute ischemic stroke admitted to 1,983 hospitals, 2.3% (30,448) were 18 to 40 years of age. Among these patients, 12.5% received tPA vs 8.8% of those >40 years of age (adjusted odds ratio [aOR] 1.63, 95% confidence interval [CI] 1.56–1.71). However, younger patients were less likely to receive brain imaging within 25 minutes (62.5% vs 71.5%, aOR 0.78, 95% CI 0.73–0.84) and to be treated with tPA within 60 minutes of hospital arrival (37.0% vs 42.8%, aOR 0.74, 95% CI 0.68–0.79). Compared to older patients, younger patients treated with tPA had a lower symptomatic intracranial hemorrhage rate (1.7% vs 4.5%, aOR 0.55, 95% CI 0.42–0.72) and lower in-hospital mortality (2.0% vs 4.3%, aOR 0.65, 95% CI 0.52–0.81).ConclusionsIn contrast to our hypothesis, younger patients with acute ischemic stroke were more likely to be treated with tPA than older patients, but they were more likely to experience delay in evaluation and treatment. Compared with older patients, younger patients had better outcomes, including fewer intracranial hemorrhages.

Background: The use of endovascular therapy (EVT) in patients with acute ischemic stroke who have large vessel occlusion has rapidly increased in the United States following pivotal trials demonstrating its benefit. Information about the contribution of interhospital transfer in improving access to EVT will help organize regional systems of stroke care. Methods: We analyzed trends of transfer-in EVT from a cohort of 1 863 693 patients with ischemic stroke admitted to 2143 Get With The Guidelines-Stroke participating hospitals between January 2012 and December 2017. We further examined the association between arrival mode and in-hospital outcomes by using multivariable logistic regression models. Results: Of the 37 260 patients who received EVT at 639 hospitals during the study period, 42.9% (15 975) arrived at the EVT-providing hospital after interhospital transfer. Transfer-in EVT cases increased from 256 in the first quarter 2012 to 1422 in the fourth quarter 2017, with sharply accelerated increases following the fourth quarter 2014 ( P Conclusions: Interhospital transfer for EVT is increasingly common and is associated with a significant delay in EVT initiation highlighting the need to develop more efficient stroke systems of care. Further evaluation to identify factors that impact EVT outcomes for transfer-in patients is warranted.

Background Regional patient characteristics, care quality, and outcomes may differ based on a variety of factors among patients hospitalized for heart failure (HF). Regional disparities in outcomes of cardiovascular disease have been suggested across various regions in the United States. This study examined whether there are significant differences by region in quality of care and short‐term outcomes of hospitalized patients with HF across the United States. Methods and Results We examined regional demographics, quality measures, and short‐term outcomes across 4 US Census Bureau regions in patients hospitalized with HF and enrolled in the GWTG‐HF (Get With The Guidelines–Heart Failure) registry from 2010 to 2016. Differences in length of stay and mortality by region were examined with multivariable logistic regression. The study included 423 333 patients hospitalized for HF in 488 hospitals. Patients in the Northeast were significantly older. Completion of achievement measures, with few exceptions, were met with similar frequency across regions. Multivariable analysis demonstrated significantly lower in‐hospital mortality in the Midwest compared with the Northeast (hazard ratio, 0.64; 95% CI, 0.51–0.8; P Conclusions Although we did not find any substantial differences by region in quality of care in patients hospitalized for HF, risk‐adjusted inpatient mortality was found to be lower in the Midwest compared with the Northeast, and may be secondary to unmeasured differences in patient characteristics, and to longer length of stay in the Northeast.

The Get With The Guidelines - Atrial Fibrillation (GWTG-AFIB) Registry uses achievement and quality measures to improve the care of patients with atrial fibrillation (AF). We sought to evaluate overall and site-level variation in attainment of these measures among sites participating in the GWTG-AFIB Registry.From the GWTG-AFIB registry, we included patients with AF admitted between 1/3/2013 and 6/30/2019. We described patient-level attainment and variation in attainment across sites of 6 achievement measures with 1) defect-free scores (percent of patients with all eligible measures attained), and 2) composite opportunity scores (percent of all eligible patient measures attained). We also described attainment of 11 quality measures at the patient-level.Among 80,951 patients hospitalized for AF (age 70±13 years, 47.0% female; CHADespite high overall attainment of care measures across GWTG-AFIB registry sites, large site variation was present with meaningful opportunities to improve AF care beyond OAC prescription, including but not limited to prescription of aldosterone antagonists in those with AF and systolic dysfunction and avoidance of non-indicated adjunctive antiplatelet therapy.

Background and Purpose— Kidney dysfunction is common among patients hospitalized for ischemic stroke. Understanding the association of kidney disease with poststroke outcomes is important to properly adjust for case mix in outcome studies, payment models and risk-standardized hospital readmission rates. Methods— In this cohort study of fee-for-service Medicare patients admitted with ischemic stroke to 1579 Get With The Guidelines-Stroke participating hospitals between 2009 and 2014, adjusted multivariable Cox proportional hazards models were used to determine the independent associations of estimated glomerular filtration rate (eGFR) and dialysis status with 30-day and 1-year postdischarge mortality and rehospitalizations. Results— Of 204 652 patients discharged alive (median age [25th–75th percentile] 80 years [73.0–86.0], 57.6% women, 79.8% white), 48.8% had an eGFR ≥60, 26.5% an eGFR 45 to 59, 16.3% an eGFR 30 to 44, 5.1% an eGFR 15 to 29, 0.6% an eGFR Conclusions— Within the first year after index hospitalization for ischemic stroke, eGFR and dialysis status on admission are associated with poststroke mortality and hospital readmissions. Kidney function should be included in risk-stratification models for poststroke outcomes.

Background and Purpose— Despite quality improvement programs such as the American Heart Association/American Stroke Association Target Stroke initiative, a substantial portion of acute ischemic stroke patients are still treated with tissue-type plasminogen activator (alteplase) later than 60 minutes from arrival. This study aims to describe the documented reasons for delays and the associations between reasons for delays and patient outcomes. Methods— We analyzed the characteristics of 55 296 patients who received intravenous alteplase in 1422 hospitals participating in Get With The Guidelines-Stroke from October 2012 to April 2015, excluding transferred patients and inpatient strokes. We assessed eligibility, medical, and hospital reasons for delays in door-to-needle time. Results— There were 27 778 patients (50.2%) treated within 60 minutes, 10 086 patients (18.2%) treated >60 minutes without documented delays, and 17 432 patients (31.5%) treated >60 minutes with one or more documented reasons for delay. Delayed door-to-needle times were associated with delayed diagnosis (36 minutes longer than those without delay in diagnosis) and hypoglycemia or seizure (34 minutes longer than without those conditions). The presence of documented delays was associated with higher odds of in-hospital mortality (odds ratio, 1.2; 95% confidence interval, 1.1–1.3) and symptomatic intracranial hemorrhage (odds ratio, 1.2; 95% confidence interval, 1.1–1.3) and lower odds of independent ambulation at discharge (odds ratio, 0.92; 95% confidence interval, 0.9–1.0) after adjusting for patient and hospital characteristics. Conclusions— Hospital and eligibility delays such as delay diagnosis and inability to determine eligibility were associated with longer door-to-needle times. Improved stroke recognition and management of acute comorbidities may help to reduce door-to-needle times.

Implantable cardioverter defibrillators (ICD) and cardiac resynchronization therapy (CRT) reduce mortality in many patients with heart failure (HF), but the current use and effectiveness of ICD/CRT in patients with chronic kidney disease (CKD) are uncertain. We examined associations between kidney function and guideline-recommended prescription of ICD/CRT in the Get With The Guidelines-Heart Failure registry, a performance improvement program for hospitalized patients with HF. We compared differences in ICD and CRT prescription between the following categories of estimated glomerular filtration rate (eGFR; mL/min/1.73m2): ≥60, 59 to 30

Randomized data suggest lenient rate control (resting heart rate110 beats/min) is noninferior to strict rate control (resting heart rate80 beats/min) in patients with atrial fibrillation (AF). However, the optimal rate control strategy in patients with AF and heart failure (HF) remains unknown. Accordingly, we performed an observational analysis using data from the Get With The Guidelines-HF Program linked with Medicare data from July 1, 2011, to September 30, 2014. Of 13,981 patients with AF and HF, 9,100 (65.0%) had strict rate control, 4,617 (33.0%) had lenient rate control, and 264 (1.9%) had poor rate control by resting heart rate on the day of discharge. After multivariable adjustment, compared with strict rate control, lenient rate control was associated with higher adjusted risks of death (hazard ratio [HR] 1.21, 95% confidence interval [CI] 1.11 to 1.33, p0.001), all-cause readmission (HR 1.09, 95% CI 1.03 to 1.15, p0.002), death or all-cause readmission (HR 1.11, 95% CI 1.05 to 1.18, p0.001), but not cardiovascular readmission (HR1.08, 95% CI 1.00 to 1.16, p = 0.051) at 90 days. Associations were comparable in patients with poor rate control and with heart rate modeled as a continuous variable. The presence or absence of reduced ejection fraction did not impact the magnitude of most observed associations. In conclusion, in patients with HF and AF, 2 of 3 patients had a heart rate that met strict-control goals at discharge. Heart rates80 beats/min were associated with adverse outcomes irrespective of left ventricular ejection fraction.

Background— The Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) trial found that initial use of ≥64 detector-row computed tomography angiography versus standard functional testing strategies (exercise ECG, stress nuclear methods, or stress echocardiography) did not improve clinical outcomes in 10 003 stable symptomatic patients with suspected coronary artery disease requiring noninvasive testing. Symptom burden and quality of life (QOL) were major secondary outcomes. Methods and Results— We prospectively collected a battery of QOL instruments in 5985 patients at baseline and 6, 12, and 24 months postrandomization. The prespecified primary QOL measures were the Duke Activity Status Index and the Seattle Angina Questionnaire frequency and QOL scales. All comparisons were made as randomized. Baseline variables were well balanced in the 2982 patients randomly assigned to computed tomography angiography testing and the 3003 patients randomly assigned to functional testing. The Duke Activity Status Index improved substantially in both groups over the first 6 months following testing, but we found no evidence for a strategy-related difference (mean difference [anatomic – functional] at 24 months of follow-up, 0.1 [95% confidence interval, –0.9 to 1.1]). Similar results were seen for the Seattle Angina Questionnaire frequency scale (mean difference at 24 months, –0.2; 95% confidence interval, –0.8 to 0.4) and QOL scale (mean difference at 24 months, –0.2; 95% confidence interval, –1.3 to 0.9). None of the secondary QOL measures showed a consistent strategy-related difference. Conclusions— In symptomatic patients with suspected coronary artery disease who required noninvasive testing, symptoms and QOL improved significantly. However, a strategy of initial anatomic testing, in comparison with functional testing, did not provide an incremental benefit for QOL over 2 years of follow-up. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01174550.

Background: Hospitalizations for acute heart failure (HF) are significant events with downstream implications for patients, as well as healthcare systems and payers. However, from anecdotal experience, both hospitalization and postdischarge courses vary significantly based on severity of presenting decompensation. Methods and Results: We compared patient and hospitalization characteristics, resource utilization, and associated outcomes, among modern era acute HF patients enrolled in the GWTG–HF (Get With the Guidelines–Heart Failure) registry between 2011 and 2016, by varying severity of their acute HF. Among over 165 000 hospitalizations included in our analysis, 2% were considered high-risk and 32% intermediate-risk for in-hospital mortality, similar to findings from 15 years prior. Further, the 1-year mortality rate was 40% among Medicare beneficiaries in GWTG–HF who survived to hospital discharge. Conclusions: The long-term outcomes among acute HF survivors remain poor and, in the context of an increasing HF burden, warrant further study of postdischarge management strategies including inpatient-to-clinic transitions and ambulatory HF systems-based care.

Glycated hemoglobin (HbA1C) is a risk factor for new onset heart failure (HF). There is however a paucity of data evaluating its association with outcomes in patients with established HF. We assessed the relation of HbA1C with outcomes among hospitalized HF patients. Among 41,776 HF patients from 263 hospitals participating to the Get with the Guidelines-HF registry between January 2009 and March 2016, we related HbA1C to outcomes (in-hospital mortality, length of hospital stay, discharge to home, 30-day mortality, 30-day readmission, and 1-year mortality), using generalized estimating equation to account for within-hospital clustering and potential confounders. There were 68% of HF patients with diabetes and median HbA1C was 7.1%. Each percent change in HbA1C was associated with higher odds of discharge to home for HbA1C levels 4 days (OR 1.10 [1.02 to 1.18]) and to be discharged home (OR 1.23 [1.14 to 1.33]). There were no significant association between HbA1C and the following outcomes: in-hospital mortality, 30-day mortality, 30-day readmission, and 1-year mortality. In conclusion, among hospitalized HF patients, HbA1C was associated with prolonged hospital stay and home discharge, but not with readmission, short-term, or intermediate-term mortality.

The GUIDE-IT (GUIDing Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure) trial prospectively compared the efficacy of an N-terminal pro-B-type natriuretic peptide (NT-proBNP)-guided heart failure treatment strategy (target NT-proBNP level 1,000 pg/ml) with optimal medical therapy alone in high-risk patients with heart failure and reduced ejection fraction. When the study was stopped for futility, 894 patients had been enrolled.The purpose of this study was to assess treatment-related quality-of-life (QOL) and economic outcomes in the GUIDE-IT trial.The authors prospectively collected a battery of QOL instruments at baseline and 3, 6, 12, and 24 months post-randomization (collection rates 90% to 99% of those eligible). The principal pre-specified QOL measures were the Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score and the Duke Activity Status Index (DASI). Cost data were collected for 735 (97%) U.S.Baseline variables were well balanced in the 446 patients randomized to the NT-proBNP-guided therapy and 448 to usual care. Both the KCCQ and the DASI improved over the first 6 months, but no evidence was found for a strategy-related difference (mean difference [biomarker-guided - usual care] at 24 months of follow-up 2.0 for DASI [95% confidence interval (CI): -1.3 to 5.3] and 1.1 for KCCQ [95% CI: -3.7 to 5.9]). Total winsorized costs averaged $5,919 higher in the biomarker-guided strategy (95% CI: -$1,795, +$13,602) over 15-month median follow-up.A strategy of NT-proBNP-guided HF therapy had higher total costs and was not more effective than usual care in improving QOL outcomes in patients with heart failure and a reduced ejection fraction. (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment [GUIDE-IT]; NCT01685840).

Background: Randomized data suggest that lenient rate control (resting heart rate Methods: Using data from the Get With The Guidelines-HF Program linked with Medicare data from July 1, 2011 to September 30, 2014, we identified patients with HF and AF and evaluated the association of heart rate at discharge with subsequent outcomes and the differential association by ejection fraction. Results: Of 13 981 patients with AF, 9 100 (65.0%) had strict rate control, 4 617 (33.0%) had lenient rate control, and 264 (1.9%) had poor rate control by resting heart rate on the day of discharge. After multivariable adjustment inclusive of medical therapy, compared with strict rate control, lenient rate control was associated with higher adjusted risks of all-cause death (HR 1.21, 95% CI 1.11-1.33, p Conclusions: Among patients with HF and AF, 2 out of 3 patients had a heart rate that met strict-control heart rate goals at discharge. Heart rates above 80 bpm at discharge were associated with adverse outcomes irrespective of left ventricular ejection fraction.

Background Adoption of electronic health record ( EHR ) systems has increased significantly across the nation. Whether EHR use has translated into improved quality of care and outcomes in heart failure ( HF ) is not well studied. Methods and Results We examined participants from the Get With The Guidelines— HF registry who were admitted with HF in 2008 (N=21 222), using various degrees of EHR implementation (no EHR , partial EHR , and full EHR ). We performed multivariable logistic regression to determine the relation between EHR status and several in‐hospital quality metrics and outcomes. In a substudy of Medicare participants (N=8421), we assessed the relation between EHR status and rates of 30‐day mortality, readmission, and a composite outcome. In the cohort, the mean age was 71±15 years, 49% were women, and 64% were white. The mean ejection fraction was 39±17%. Participants were admitted to hospitals with no EHR (N=1484), partial EHR (N=13 473), and full EHR (N=6265). There was no association between EHR status and several quality metrics (aside from β blocker at discharge) or in‐hospital outcomes on multivariable adjusted logistic regression ( P >0.05 for all comparisons). In the Medicare cohort, there was no association between EHR status and 30‐day mortality, readmission, or the combined outcome. Conclusions In a large registry of hospitalized patients with HF, there was no association between degrees of EHR implementation and several quality metrics and 30‐day postdischarge death or readmission. Our results suggest that EHR may not be sufficient to improve HF quality or related outcomes.

Background— Previous studies have reported that black patients undergoing coronary artery bypass surgery had worse outcomes than white patients, even after accounting for patient factors. The degree to which clinician, hospital, and care factors account for these outcome differences remains unclear. Methods and Results— We evaluated procedural outcomes in 11 697 blacks and 136 362 whites undergoing isolated coronary artery bypass surgery at 663 Society of Thoracic Surgery Database participating sites (January 1, 2010 to June 30, 2011) adjusted for patients’ clinical and socioeconomic features, hospital and surgeon effects, and care processes (internal mammary artery graft and perioperative medications use). Relative to whites, blacks undergoing coronary artery bypass surgery were younger, yet had higher comorbidities and more adverse presenting features. Blacks were also more likely to be treated at hospitals with higher risk-adjusted mortality. The use of internal mammary artery was marginally lower in blacks than in whites (93.3% versus 92.2%, P P P Conclusions— The risks of procedural mortality and morbidity after coronary artery bypass surgery were higher among black patients than among white patients. These differences were in part accounted for by patient comorbidities, socioeconomic status, and surgeon, hospital, and care factors, as well, as suggested by the reduction in the strength of the race-outcomes association. However, black race remained an independent predictor of outcomes even after accounting for these differences.

Background In the SAFE-PCI for Women trial, patient preference for radial access for future procedures was greater than for femoral access. We sought to assess whether radial or femoral access impacts formal measures of quality-of-life (QOL) among women undergoing cardiac catheterization. Methods We assessed QOL using European quality of life–5 dimensions (EQ-5D) and EQ visual analog scale (EQ-VAS) scores among 304 women randomized to radial or femoral arteriotomy in the SAFE-PCI for Women trial at sites with QOL substudy approval. Patient surveys were administered at baseline, hospital discharge, and 30 days (for percutaneous coronary intervention patients). Results Women randomized to both treatments had similar EQ-5D index and EQ-VAS scores at baseline, hospital discharge, and 30-day follow-up. After adjustment for baseline scores, there was no effect of assigned treatment on EQ-5D (discharge 0.004; 95% CI −0.03 to 0.04; 30 days −0.03; 95% CI −0.09 to 0.02) or EQ-VAS (discharge −1.31; 95% CI −4.74 to 2.12; 30 days −2.10; 95% CI −8.92 to 4.71) scores. At discharge, 60.5% versus 63.5% ( P = .60) of patients in radial and femoral groups were free from access site pain; at 30 days, rates were 85.7% versus 77.6% ( P = .30), respectively. Patient preference for the same access strategy for repeat procedures was greater in the radial versus femoral group (77.2% vs 26.8%; P Conclusions Using established QOL instruments, we did not measure any difference in QOL or functional status according to access site strategy in women undergoing cardiac catheterization, yet patient preference for the radial approach was significantly greater. Other factors influencing patient choice for radial access should be investigated.

Purpose: Interhospital transfer for endovascular therapy (EVT) is increasingly frequent. We sought to compare the patient characteristics and in-hospital outcomes of EVT by arrival groups (transfer-in vs. front-door). Methods: We analyzed data from 22,881 acute ischemic stroke (AIS) patients treated with EVT in Get With The Guideline (GWTG)-Stroke from January 2012 through September 2016 at 553 hospitals. Patient level characteristics were compared by arrival groups. Multivariable logistic regression models were generated to examine the association between arrival mode and in-hospital outcomes. Results: Of 22,881 patients receiving EVT 41.5% (9,510) arrived to the EVT providing hospital after interhospital transfer. Transfer-in patients were more likely to be younger and of white race, with arrival during off-hours and lower initial recorded blood pressure. Transfer-in patients had significantly longer last known well to EVT initiation time (296 min vs 224 min, absolute standardized difference 67.09) but were more likely to have door to EVT initiation time of ≤ 90 minutes (Table 1). In-hospital outcomes were worse for transfer-in EVT patients in unadjusted analyses but in the risk adjusted models, there was no difference in the rates of in-hospital mortality and symptomatic intracranial hemorrhage. After risk adjustment, transfer-in patients were still less likely to have independent ambulation at discharge and discharged to home (Table 1). Conclusions: Interhospital transfer of AIS patients for endovascular therapy is associated with significant delay to treatment. In spite of similar risk adjusted in-hospital mortality and symptomatic intracerebral hemorrhage rates, transfer-in patients are less likely to have favorable discharge functional status.

Background: Intravenous recombinant tissue-type plasminogen activator (rt-PA) administration improves outcomes in acute ischemic stroke. However, young patients ( Methods: We analyzed data from the large national Get With The Guidelines–Stroke registry for acute ischemic stroke patients hospitalized between January 2009 and September 2015. Multivariable models with generalized estimating equations (GEE) were used to test for differences between younger (age 18-40) and older (age > 40) acute ischemic stroke patients, controlling for patient and hospital characteristics including stroke severity. Results: Of 1,320,965 AIS patients admitted to participating hospitals, 2.3% (30,448) were aged 18-40. Among these patients, 12.5% received rt-PA versus 8.8% of those aged >40 (p Conclusions: Young acute ischemic stroke patients did not receive rt-PA treatment at lower rates than older patients. Outcomes were better and the rate of symptomatic intracranial hemorrhage was lower in the young patients. However, younger patients had significantly longer door-to-CT and DTN times, providing an opportunity to improve the care of these patients.

Background: Despite quality improvement programs such as the American Heart Association/American Stroke Association Target_Stroke initiative, a substantial portion of acute ischemic stroke patients are still treated with alteplase later than 60 minutes, for unclear reasons. This study aims to describe the documented reasons for delays as well as the associations between reasons for delays and patient outcomes. Methods: We analyzed 55,296 patients who received intravenous alteplase in 1,422 hospitals participating in Get With The Guidelines-Stroke from October 2012 to April 2015, excluding transferred patients and inpatient strokes. We assessed eligibility, medical, and hospital reasons for delays in door-to-needle time (DTN). Multivariable models were used to evaluate associations between reasons for delays, time lost, and hospital discharge outcomes, controlling for patient and hospital characteristics. Results: There were 27,778 (50.2%) patients treated within 60 minutes, 10,086 (18.2%) treated in more than 60 minutes without documented delays, and 17,432 (31.5%) treated in more than 60 minutes with one or more documented reasons for delay. The longest DTN times were associated with inability to determine eligibility, delay in diagnosis, further diagnostic evaluation for hypoglycemia or seizure, management of emergent medical conditions and initial patient refusal (Table). One or more reason for delays was associated with in-hospital mortality (OR 1.2; 95CI 1.1-1.3), symptomatic intracranial hemorrhage (OR 1.2; 95CI 1.1-1.3), and lower odds of independent ambulation at discharge (OR 0.92; 95CI 0.9-1.0). Conclusions: Hospital and eligibility delays such as delay in diagnosis and inability to determine eligibility are common and are associated with longer DTN and poorer outcomes. Improved stroke recognition and management of acute comorbidities may help to reduce DTN times and improve outcomes.

Catheter ablation is more effective than drug therapy in restoring sinus rhythm in patients with atrial fibrillation (AF), but its incremental effect on long-term quality of life (QOL) is uncertain.To determine whether catheter ablation is more beneficial than conventional drug therapy for improving QOL in patients with AF.An open-label randomized clinical trial of catheter ablation vs drug therapy in 2204 symptomatic patients with AF older than 65 years or 65 years or younger with at least 1 risk factor for stroke. Patients were enrolled from November 2009 to April 2016 from 126 centers in 10 countries. Follow-up ended in December 2017.Pulmonary vein isolation, with additional ablation procedures at the discretion of the investigators, for the catheter ablation group (n = 1108) and standard rhythm and/or rate-control drugs selected and managed by investigators for the drug therapy group (n = 1096).Prespecified co-primary QOL end points at 12 months, including the Atrial Fibrillation Effect on Quality of Life (AFEQT) summary score (range, 0-100; 0 indicates complete disability and 100 indicates no disability; patient-level clinically important difference, ≥5 points) and the Mayo AF-Specific Symptom Inventory (MAFSI) frequency score (range, 0-40; 0 indicates no symptoms and 40 indicates the most severe symptoms; patient-level clinically important difference, ≤-1.6 points) and severity score (range, 0-30; 0 indicates no symptoms and 30 indicates the most severe symptoms; patient-level clinically important difference, ≤-1.3 points).Among 2204 randomized patients (median age, 68 years; 1385 patients [63%] were men, 946 [43%] had paroxysmal AF, and 1256 [57%] had persistent AF), the median follow-up was 48.5 months, and 1968 (89%) completed the trial. The mean AFEQT summary score was more favorable in the catheter ablation group than the drug therapy group at 12 months (86.4 points vs 80.9 points) (adjusted difference, 5.3 points [95% CI, 3.7-6.9]; P .001). The mean MAFSI frequency score was more favorable for the catheter ablation group than the drug therapy group at 12 months (6.4 points vs 8.1 points) (adjusted difference, -1.7 points [95% CI, -2.3 to -1.2]; P .001) and the mean MAFSI severity score was more favorable for the catheter ablation group than the drug therapy group at 12 months (5.0 points vs 6.5 points) (adjusted difference, -1.5 points [95% CI, -2.0 to -1.1]; P .001).Among patients with symptomatic atrial fibrillation, catheter ablation, compared with medical therapy, led to clinically important and significant improvements in quality of life at 12 months. These findings can help guide decisions regarding management of atrial fibrillation.ClinicalTrials.gov Identifier: NCT00911508.

Background Tricuspid valve (TV) infective endocarditis (IE) accounts for 15% of IE cases and usually is treated medically. Surgical intervention is rare, and understanding of treatment options is based on small series of patients. The purpose of this study was to describe the population and outcomes for isolated TV IE using The Society of Thoracic Surgeons Adult Cardiac Database. Methods Between 2002 and 2009, 910 operations for TV IE were performed. Procedures included replacement, repair, and valvectomy. Healed IE was present in 31.4% (n = 286), and active IE, in 68.5% (n = 624). Baseline patient characteristics as well as operative mortality and morbidity were analyzed, and univariate statistical differences were evaluated by Kruskal-Wallis test and stratum-adjusted Mantel-Haenszel χ 2 tests. Results The median age was 40 years, with 50.6% male. Replacement of the TV was the most common procedure (n = 490; 53.8%), followed by TV repair (n = 354; 38.9%) and valvectomy (n = 66; 7.2%). Overall operative mortality was 7.3%, with no significant difference in mortality among valvectomy 12%, repair 7.6%, and replacement 6.3% ( p = 0.34). Compared with the active group, healed patients experienced a trend toward lower operative mortality (4.2% versus 8.6%; p = 0.06), lower complication rates (35.6% versus 51.4%; p = 0.0004), and shorter overall length of stay (12 versus 22 days; p Conclusions Isolated TV operation for IE is a rare clinical entity with a similar operative mortality to left-sided IE operations. Repair and replacement of the TV had similar perioperative mortality. Patients in the healed TV IE group demonstrated lower complication rates, length of stay, and a trend toward decreased mortality.

Background: The longitudinal success of the heart failure (HF) patient with a left ventricular assist device (LVAD) depends on medications to maintain the device, such as antithrombotic agents to prevent pump thrombosis and antihypertensives to reduce stroke risk. However, the role of traditional, evidence-based HF medications for patients with concurrent LVAD support is not well known. This study aimed to determine use, temporal trends, and factors associated with prescription of HF medications at discharge among patients with advanced HF with and without LVADs, and to examine patient and hospital-level factors associated with HF medication prescription among LVAD recipients. Methods: We conducted a retrospective, observational analysis of 4,580 advanced HF patients from 215 hospitals participating in the Get With The Guidelines-Heart Failure registry from January 2009 to March 2015. We examined patterns of HF medication use at hospital discharge among patients with an in-hospital (n=258) or prior (n=326) LVAD implant, and those with advanced HF without an LVAD, as defined by a reduced left ventricular ejection fraction and intravenous inotrope or vasopressin antagonist receipt (n=3,996). Results: For beta-blocker and angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACE/ARB), discharge prescriptions were 58.9% and 53.5% for new LVAD recipients, 62.9% and 51.4% for prior LVAD recipients, and 78.7% and 60.7% for patients without LVAD support, respectively (p Conclusion: Traditional HF therapies are commonly prescribed to LVAD recipients, although less frequently than to advanced HF patients without LVAD support. Aldosterone antagonists are prescribed increasingly to LVAD patients. Further research is needed on the optimal medical regimen for patients with LVADs.

Real-world use of traditional heart failure (HF) medications for patients with left ventricular assist devices (LVADs) is not well known.We conducted a retrospective, observational analysis of 1,887 advanced HF patients with and without LVADs from 32 LVAD hospitals participating in the Get With The Guidelines-Heart Failure registry from January 2009 to March 2015. We examined HF medication prescription at discharge, temporal trends, and predictors of prescription among patients with an in-hospital (n = 258) or prior (n = 171) LVAD implant, and those with advanced HF but no LVAD, as defined by a left ventricular ejection fraction ≤25% and in-hospital receipt of intravenous inotropes or vasopressin receptor antagonists (n = 1,458).For β-blocker and angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACEI/ARB), discharge prescriptions were 58.9% and 53.5% for new LVAD patients, 53.8% and 42.9% for prior LVAD patients, and 73.4% and 63.2% for patients without LVAD support, respectively (both P.0001). Aldosterone antagonist prescription quadrupled among LVAD patients during the study period (P.0001), whereas ACEI/ARB use decreased nearly 20 percentage points (60.0% to 41.4%, P = .0003). In the multivariable analysis of LVAD patients, patient age was inversely associated with β-blocker, ACEI/ARB, and aldosterone antagonist prescription.Traditional HF therapies were moderately prescribed at discharge to patients with LVADs and were more frequently prescribed to patients with advanced HF without LVAD support. Moderate prescription rates suggest clinical uncertainty in the use of antiadrenergic medication in this population. Further research is needed on the optimal medical regimen for patients with LVADs.

Obesity has become a major epidemic in the United States. Although research suggests obesity does not increase major morbidity or mortality after thoracic operations, it likely results in greater use of health care resources.We examined all patients in The Society of Thoracic Surgeons General Thoracic Surgery database with primary lung cancer who underwent lobectomy from 2006 to 2010. We investigated the impact of body mass index (BMI) on total operating room time using a linear mixed-effects regression model and multiple imputations to account for missing data. Secondary outcomes included postoperative length of stay and 30-day mortality. Covariates included age, sex, race, forced expiratory volume, smoking status, Zubrod score, prior chemotherapy or radiation, steroid use, number of comorbidities, surgical approach, hospital lobectomy volume, hospital percent obesity, and the addition of mediastinoscopy or wedge resection.A total of 19,337 patients were included. The mean BMI was 27.3 kg/m2, with 4,898 patients (25.3%) having a BMI of 30 kg/m2 or greater. The mean total operating room time, length of stay, and 30-day mortality were 240 minutes, 6.7 days, and 1.8%, respectively. For every 10-unit increase in BMI, mean operating room time increased by 7.2 minutes (range, 4.8 to 8.4 minutes; p0.0001). Higher hospital lobectomy volume and hospital percentage of obese patients did not affect the association between BMI and operative time. Body mass index was not associated with 30-day mortality or increased length of stay.Increased BMI is associated with increased total operating room time, regardless of institutional experience with obese patients.

Objective Despite growing awareness of the clinical significance of atrial fibrillation (AF) and observational data demonstrating the safety and efficacy of surgical therapy, AF ablation is variably performed among patients with AF undergoing cardiac surgery. We examined the national trends of surgical ablation and perioperative outcomes for stand-alone surgical ablation of AF. Methods Using the Society of Thoracic Surgeons Adult Cardiac Surgery Database, 91,801 (2005-2010) surgical AF ablations were performed of which 4893 (5.3%) were stand-alone procedures. The outcomes of 854 propensity-matched pairs having "on" versus "off" cardiopulmonary bypass stand-alone ablation were compared. Results The percentage of patients with preoperative AF increased from 2005 to 2010 (from 10.0% to 12.2%). Overall, 40.6% of patients with AF underwent concomitant surgical ablation—a significant decline of 1.6% from 2005 to 2010. The number of stand-alone surgical ablations increased significantly from 552 to 1041 cases (2005-2010). Overall, the stand-alone group had a mean age of 60 years, 71% were men, and 80% were treated "off" cardiopulmonary bypass. The "on" cardiopulmonary bypass group had significantly more pulmonary disease, diabetes, and congestive heart failure. Overall, the operative mortality and stroke rate was 0.7% for each. After propensity matching, the "off" cardiopulmonary bypass group underwent significantly fewer reoperations for bleeding and had a lower incidence of prolonged ventilation and shorter hospitalization. New pacemaker implantation was low, without group differences. Conclusions The prevalence of AF in patients undergoing cardiac surgery has increased, as has the number of stand-alone surgical ablations. The treatment of concomitant disease declined slightly. Isolated surgical ablation is safe, performed "on" or "off" cardiopulmonary bypass. These results support consideration of surgical AF ablation as an alternative to percutaneous ablation for patients with lone AF.

Objective Coronary artery bypass grafting (CABG) is the operation most commonly performed by cardiac surgeons. There are few contemporary data examining evolving patient characteristics and surgical outcomes of isolated CABG. We used the Society of Thoracic Surgeons adult cardiac surgery database to characterize trends in patient characteristics and outcomes after CABG over the past decade. Methods From 2000 to 2009, 1,497,254 patients underwent isolated primary CABG at Society of Thoracic Surgeons participating institutions. Demographics, operative characteristics, and postoperative outcomes were assessed, and risk-adjusted outcomes were calculated. Results Compared with the year 2000, patients undergoing isolated primary CABG in 2009 were more likely to have diabetes mellitus (33% vs 40%) and hypertension (71% vs 85%). There were clinically insignificant differences in age, gender, and body surface area. Between 2000 and 2009, there has been a 6.3% and 19.5% increase in the preoperative use of aspirin and beta-blockers, respectively. Between 2004 and 2009, there was a 7.8% increase in the use of angiotension-converting enzyme inhibitors preoperatively. Furthermore, between 2005 and 2009 there was a 3.8% increase in the use of statins preoperatively. The median number of distal anastomoses performed was unchanged between 2000 and 2009 (3; interquartile range, 2–4). There was a significant increase in the use of the internal thoracic artery (88% in 2000 vs 95% in 2009). The predicted mortality rates of 2.3% were consistent between 2000 and 2009. The observed mortality rate over this period declined from 2.4% in 2000 to 1.9% in 2009 representing a relative risk reduction of 24.4%. The incidence of postoperative stroke decreased significantly from 1.6% to 1.2%, representing a risk reduction of 26.4%. There was also a 9.2% relative reduction in the risk of reoperation for bleeding and a 32.9% relative risk reduction in the incidence of sternal wound infection. Conclusions Over the past decade, the risk profile of patients undergoing CABG has changed, with fewer smokers, more diabetic patients, and better medical therapy characterizing patients referred for surgical coronary revascularization. The left internal thoracic artery is nearly universally used and outcomes have improved substantially, with a significant decline in postoperative mortality and morbidity.

OBJECTIVE:Previous analyses have suggested center volume is associated with outcome in children undergoing heart surgery. However, data are limited regarding potential mediating factors, including the relationship of center volume with postoperative complications and mortality in those who suffer a complication. We examined this association in a large multicenter cohort.METHODS:Children 0 to 18 years undergoing heart surgery at centers participating in the Society of Thoracic Surgeons Congenital Heart Surgery Database (2006–2009) were included. In multivariable analysis, we evaluated outcomes associated with annual center volume, adjusting for patient factors and surgical risk category.RESULTS:A total of 35 776 patients (68 centers) were included. Overall, 40.6% of patients had ≥1 complication, and the in-hospital mortality rate was 3.9%. The mortality rate in those patients with a complication was 9.0%. In multivariable analysis, lower center volume was significantly associated with higher in-hospital mortality. There was no association of center volume with the rate of postoperative complications, but lower center volume was significantly associated with higher mortality in those with a complication (P = .03 when volume examined as a continuous variable; odds ratio in centers with 350 cases per year = 1.59 [95% confidence interval: 1.16–2.18]). This association was most prominent in the higher surgical risk categories.CONCLUSIONS:These data suggest that the higher mortality observed at lower volume centers in children undergoing heart surgery may be related to a higher rate of mortality in those with postoperative complications, rather than a higher rate of complications alone.

Background Long-term evaluation of cardiothoracic surgical outcomes is a major goal of The Society of Thoracic Surgeons (STS). Linking the STS Database to the Social Security Death Master File (SSDMF) allows for the verification of "life status." This study demonstrates the feasibility of linking the STS Database to the SSDMF and examines longitudinal survival after cardiac operations. Methods For all operations in the STS Adult Cardiac Surgery Database performed in 2008 in patients with an available Social Security Number, the SSDMF was searched for a matching Social Security Number. Survival probabilities at 30 days and 1 year were estimated for nine common operations. Results A Social Security Number was available for 101,188 patients undergoing isolated coronary artery bypass grafting, 12,336 patients undergoing isolated aortic valve replacement, and 6,085 patients undergoing isolated mitral valve operations. One-year survival for isolated coronary artery bypass grafting was 88.9% (6,529 of 7,344) with all vein grafts, 95.2% (84,696 of 88,966) with a single mammary artery graft, 97.4% (4,422 of 4,540) with bilateral mammary artery grafts, and 95.6% (7,543 of 7,890) with all arterial grafts. One-year survival was 92.4% (11,398 of 12,336) for isolated aortic valve replacement (95.6% [2,109 of 2,206] with mechanical prosthesis and 91.7% [9,289 of 10,130] with biologic prosthesis), 86.5% (2,312 of 2,674) for isolated mitral valve replacement (91.7% [923 of 1,006] with mechanical prosthesis and 83.3% [1,389 of 1,668] with biologic prosthesis), and 96.0% (3,275 of 3,411) for isolated mitral valve repair. Conclusions Successful linkage to the SSDMF has substantially increased the power of the STS Database. These longitudinal survival data from this large multi-institutional study provide reassurance about the durability and long-term benefits of cardiac operations and constitute a contemporary benchmark for survival after cardiac operations.

OBJECTIVE: Recently, there has been a shift toward care of children undergoing heart surgery in dedicated pediatric cardiac intensive care units (CICU). The impact of this trend on patient outcomes is unclear. We evaluated postoperative outcomes associated with a CICU versus other ICU models. PATIENTS AND METHODS: Society of Thoracic Surgeons Congenital Heart Surgery Database participants (2007–2009) who completed an ICU survey were included. In multivariable analysis, we evaluated outcomes associated with a CICU versus other ICUs, adjusting for center volume, patient factors, and Society of Thoracic Surgeons–European Association for Cardiothoracic Surgery surgical risk category. RESULTS: A total of 20 922 patients (47 centers; 25 with a CICU) were included. Overall unadjusted mortality was 3.8%, median length of stay was 6 days (interquartile range: 4–13), and 21% had 1 or more complications. In multivariable analysis, there was no difference in mortality comparing CICUs versus other ICUs (odds ratio: 0.88 [95% confidence interval: 0.65–1.19]). In stratified analysis, CICUs were associated with lower mortality only among those in Society of Thoracic Surgeons–European Association for Cardiothoracic Surgery category 3 (odds ratio: 0.47 [95% confidence interval: 0.25–0.86]), primarily related to atrioventricular canal repair and arterial switch operation. There was no difference in length of stay or complications overall or in stratified analysis. CONCLUSIONS: We were not able to detect a difference in postoperative morbidity or mortality associated with the presence of a dedicated CICU for children undergoing heart surgery. There may be a survival benefit in certain subgroups .

Background Aortic dissection as a complication of cardiac surgery is a rare but often lethal event. We sought to determine the frequency of this complication in the STS (Society of Thoracic Surgeons) database as well as the outcomes of patients who suffer intraoperative aortic dissection. We then developed a model to identify preoperative characteristics and intraoperative factors associated with the complication. Methods All patients from the STS database who underwent coronary artery bypass grafting, aortic valve surgery, or mitral valve surgery were included. Exclusion criteria included any patient who had aortic dissection listed as a reason for urgent or emergent operation. Data collected were then analyzed to describe the frequency of aortic dissection as a complication as well as its consequences. We then analyzed a more recent era that included information on arterial cannulation site (femoral-other versus aortic) to identify risk factors for aortic dissection. Results Of 2,219,991 patients analyzed, 1,294 suffered aortic dissection as a complication of their surgery, for an incidence of 0.06%. This complication frequently led to catastrophic results, with 615 of 1,294 (48%) operative mortality. A logistic regression model was created based on 2004 to 2007 STS data. Of 680,025 patients analyzed, 436 patients suffered an aortic dissection. The analysis yielded nine significant risk factors including femoral arterial cannulation, preoperative steroids, and Asian race; the presence of diabetes appeared to be protective. Conclusions Aortic dissection is a rare but catastrophic complication of cardiac surgery. Femoral cannulation is associated with an increased frequency of this complication.

BackgroundSeveral single-institution series have demonstrated that compared with open thoracotomy, video-assisted thoracoscopic lobectomy may be associated with fewer postoperative complications. In the absence of randomized trials, we queried the Society of Thoracic Surgeons database to compare postoperative mortality and morbidity following open and video-assisted thoracoscopic lobectomy. A propensity-matched analysis using a large national database may enable a more comprehensive comparison of postoperative outcomes.MethodsAll patients having lobectomy as the primary procedure via thoracoscopy or thoracotomy were identified in the Society of Thoracic Surgeons database from 2002 to 2007. After exclusions, 6323 patients were identified: 5042 having thoracotomy, 1281 having thoracoscopy. A propensity analysis was performed, incorporating preoperative variables, and the incidence of postoperative complications was compared.ResultsMatching based on propensity scores produced 1281 patients in each group for analysis of postoperative outcomes. After video-assisted thoracoscopic lobectomy, 945 patients (73.8%) had no complications, compared with 847 patients (65.3%) who had lobectomy via thoracotomy (P < .0001). Compared with open lobectomy, video-assisted thoracoscopic lobectomy was associated with a lower incidence of arrhythmias [n = 93 (7.3%) vs 147 (11.5%); P = .0004], reintubation [n = 18 (1.4%) vs 40 (3.1%); P = .0046], and blood transfusion [n = 31 (2.4%) vs n = 60 (4.7%); P = .0028], as well as a shorter length of stay (4.0 vs 6.0 days; P < .0001) and chest tube duration (3.0 vs 4.0 days; P < .0001). There was no difference in operative mortality between the 2 groups.ConclusionsVideo-assisted thoracoscopic lobectomy is associated with a lower incidence of complications compared with lobectomy via thoracotomy. For appropriate candidates, video-assisted thoracoscopic lobectomy may be the preferred strategy for appropriately selected patients with lung cancer.

The purpose of this study is to examine trends in mitral valve (MV) repair and replacement surgery using The Society of Thoracic Surgeons Adult Cardiac Surgery Database (STS ACSD).The study population included isolated mitral valve operations performed between January 2000 and December 2007 at 910 hospitals participating in the STS ACSD. Patients with endocarditis, prior cardiac operation, shock, emergency operation, and concomitant coronary artery bypass graft or aortic valve surgery were excluded.During the 8-year study period, 58,370 patients underwent isolated primary MV operations. For patients with isolated mitral regurgitation (n = 47,126), the rate of MV repair (versus replacement) increased from 51% to 69% (p0.0001). Among patients having replacement (n = 24,404), there has been a pronounced decline in the use of mechanical valves: 68% to 37% (p0.0001). The operative mortality for MV replacement was consistently higher than that for repair (3.8% versus 1.4%), a finding that persisted after risk-adjustment (adjusted odds ratio 0.52, 95% confidence interval: 0.45 to 0.59; p0.0001). Among patients having elective isolated MV repair (n = 28,140), the operative mortality was 1.2%. For asymptomatic (class I) patients, operative mortality was 0.6%.This study documents several important trends in MV surgery, including the progressive adoption of mitral valve repair and increasing use of bioprosthetic replacement valves. Operative risks of MV repair are significantly lower than those for MV replacement. Operative mortality for isolated elective mitral valve repair is 1% in contemporary clinical practice.

The expression of carbonic anhydrase XII (CA12), a gene that encodes a zinc metalloenzyme responsible for acidification of the microenvironment of cancer cells, is highly correlated with estrogen receptor α (ERα) in human breast tumors. Here, we show that CA12 is robustly regulated by estrogen via ERα in breast cancer cells, and that this regulation involves a distal estrogen-responsive enhancer region. Upon the addition of estradiol, ERα binds directly to this distal enhancer in vivo, resulting in the recruitment of RNA polymerase II and steroid receptor coactivators SRC-2 and SRC-3, and changes in histone acetylation. Mutagenesis of an imperfect estrogen-responsive element within this enhancer region abolishes estrogen-dependent activity, and chromosome conformation capture and chromatin immunoprecipitation assays show that this distal enhancer communicates with the transcriptional start site of the CA12 gene via intrachromosomal looping upon hormone treatment. This distal enhancer element is observed in the homologous mouse genomic sequence, and the expression of the mouse homologue, Car12, is rapidly and robustly stimulated by estradiol in the mouse uterus in vivo, suggesting that the ER regulation of CA12 is mechanistically and evolutionarily conserved. Our findings highlight the crucial role of ER in the regulation of the CA12 gene, and provide insight into the transcriptional regulatory mechanism that accounts for the strong association of CA12 and ER in human breast cancers. [Cancer Res 2008;68(9):3505–15]

Equol is a metabolite produced in vivo from the soy phytoestrogen daidzein by the action of gut microflora. It is known to be estrogenic, so human exposure to equol could have significant biological effects. Equol is a chiral molecule that can exist as the enantiomers R-equol and S-equol. To study the biological activity of racemic (+/-)-equol, as well as that of its pure enantiomers, we developed an efficient and convenient method to prepare (+/-)-equol from available isoflavanoid precursors. Furthermore, we optimized a method to separate the enantiomers of equol by chiral HPLC, and we studied for the first time, the activities of the enantiomers on the two estrogen receptors, ERalpha and ERbeta. In binding assays, S-equol has a high binding affinity, preferential for ERbeta (K(i)[ERbeta]=16 nM; beta/alpha=13 fold), that is comparable to that of genistein (K(i)[ERbeta]=6.7 nM; beta/alpha=16), whereas R-equol binds more weakly and with a preference for ERalpha (K(i)[ERalpha]=50 nM; beta/alpha=0.29). All equol isomers have higher affinity for both ERs than does the biosynthetic precursor daidzein. The availability and the in vitro characterization of the equol enantiomers should enable their biological effects to be studied in detail.

Allosteric communication between interacting molecules is fundamental to signal transduction and many other cellular processes. To better understand the relationship between nuclear receptor (NR) ligand positioning and the formation of the coactivator binding pocket, we investigated the determinants of ligand selectivity between the two estrogen receptor subtypes ERalpha and ERbeta. Chimeric receptors and structurally guided amino acid substitutions were used to demonstrate that distinct "hot spot" amino acids are required for ligand selectivity. Residues within the ligand binding pocket as well as distal secondary structural interactions contribute to subtype-specific positioning of the ligand and transcriptional output. Examination of other NRs suggests a mechanism of communication between the ligand and coactivator binding pockets, accounting for partial agonist and dimer-specific activity. These results demonstrate the importance of long-range interactions in the transmission of information through the ligand binding domain as well as in determining the ligand selectivity of closely related NR receptor subtypes.

Estrogens exert their regulatory transcriptional effects, which can be stimulatory or repressive, at diverse gene sites via two estrogen receptors, ERalpha and ERbeta. Since these two ERs have different tissue distributions, ligands that have the capacity to selectively activate or inhibit these two ERs would be useful in elucidating the biology of these two receptors and might assist in the development of estrogen pharmaceuticals with improved tissue selectivity. We have developed several ligands that showed ERalpha or ERbeta selectivity at promoter-gene sites containing consensus estrogen response elements (EREs): ERalpha-selective agonist (propyl-pyrazole-triol (PPT)), ERalpha-selective antagonist (methyl-piperidino-pyrazole (MPP)), ERbeta-potency selective agonist (diarylpropionitrile (DPN)) and ERbeta-selective antagonist/ERalpha-agonist (R,R-tetrahydrochrysene (R,R-THC)). In this study, we have examined the activity of these compounds at a range of gene sites where ER stimulates gene expression through non-consensus EREs (complement C3), or multiple half-EREs (NHE-RF/EBP50), or by tethering to DNA via other proteins (TGF beta3 and progesterone receptor A/AP-1), and at gene sites where ER represses gene transcription (interleukin-6). At all of these genes, PPT showed full stimulation through ERalpha while displaying no agonism through ERbeta. MPP antagonized estradiol actions on gene transactivation and transrepression through ERalpha, with little or no effect on transcription mediated through ERbeta. DPN displayed subtype-selective agonism, being ca. 30-fold more potent through ERbeta. R,R-THC was a complete antagonist through ERbeta and displayed agonism through ERalpha, the level of which was promoter dependent. Because these ligands maintain their agonist or antagonist character and ER subtype-selectivity at gene sites of diverse nature, where estradiol is either stimulatory or inhibitory, these compounds should prove useful in elucidating the biological functions of ERalpha and ERbeta.

The actions of estrogens are mediated through the two estrogen receptors, ERalpha and ERbeta. Compounds that interact selectively with ERalpha or ERbeta are of interest because they could be used to explore the biological roles of these ER subtypes and they might be interesting estrogen pharmaceuticals. In a new approach to develop ER subtype-selective ligands, we have embellished the 1,1-diarylethylene motif, common to many nonsteroidal estrogens, with various bridged bicyclic or tricyclic cores, including ones based on bicyclo[3.3.1]nonane, bicyclo[2.2.1]heptane, and selected bi- and tricyclic terpenoids. This design leads to three-dimensional ER ligands of unusual structure that we have used to probe the size and shape of the ligand binding pocket of ERalpha and ERbeta. Many of these compounds have high binding affinities, with the best having a bicyclo[3.3.1]nonane core and binding 3-5 times better than estradiol to both ER subtypes. Some of the compounds show significant affinity selectivity in favor of ERbeta (4- to 5-fold), and in cell-based assays for transcriptional activity most are partial agonists on ERalpha and full antagonists on ERbeta.

An effective, unprecedented replacement of the prototypical phenolic ‘A-ring’ of estrogens with an oxime and a hydroxy-moiety of the salicylaldoxime derivative 3,4-diphenyl-substituted ( 1a ) opened the way to study structure–activity relationships of a new class of estrogen receptor (ER)-ligands. Herein, we present a study of the ER binding properties and transcriptional activities of analogues of 3,4-diphenylsalicylaldoxime ( 1a ). The introduction of p -OH and p -OMe groups on the phenyl substituents of 1a , as in compounds 1b – g , results in unique structure–activity profiles. The preparation of the hetero-disubstituted compounds ( 1b – e ) was accomplished by a sequential introduction of different 3- and 4-aryl groups, obtained by exploiting the different reactivity of the bromine versus chlorine substituents on the precursor, 2-bromo-3-chloronitrobenzene ( 5 ), in the palladium-catalyzed cross-coupling reactions. The results of the biological tests show that the introduction of one hydroxy-group on the 3-phenyl substituent of the lead compound 1a improved the binding affinity on ERβ ( 1c ), whereas the introduction of the same group on the 4-phenyl substituent of 1a gave a compound ( 1e ) with better affinity properties on ERα. The introduction of two hydroxyl groups in the para -position of both phenyl substituents of 1a , as in 1g , lowered the binding on both receptor subtypes. In transcription assays, the ERα agonist character of this class of ligands is enhanced by the presence of a p -hydroxy or p -methoxy in the ‘distal’ phenyl ring, whereas substitution on the other phenyl ring does not substantially modify the partial agonist character of 1a . Thus, results from the binding and transcription assays illustrate that this class of ER ligands has a distinct structure–activity profile on the two ER subtypes, being potent nearly full agonists on ERα and weak, partial antagonists on ERβ.

To develop compounds that are antagonists on ER(alpha), but not ER(beta), we have added basic side-chains typically found in nonsteroidal antiestrogens to pyrazole compounds that bind with much higher affinity to ER(alpha) than to ER(beta). In this way we have developed basic side-chain pyrazoles (BSC-pyrazoles) that are high affinity, potent, selective antagonists on ER(alpha). These BSC-pyrazoles are themselves inactive on ER(alpha) and ER(beta), and they antagonize E2 stimulation by ER(alpha) only. We investigated seven basic side-chain substituents on various alkyl-triaryl-substituted pyrazoles, and the most ER(alpha)-selective compound was methyl-piperidino-pyrazole (MPP). ER(alpha)-selective antagonism was observed on diverse reporter-promoter gene constructs containing estrogen response elements that are consensus, nonconsensus (pS2), or comprised of multiple half-estrogen response elements (NHERF/EBP50) and on genes in which ER works indirectly by tethering to other DNA-bound proteins (TGF(beta)3). In contrast to these BSC-pyrazoles, the antiestrogens trans-hydroxytamoxifen, raloxifene, and ICI 182,780 suppress E2 activity via both ER(alpha) and ER(beta). The most effective BSC-pyrazole, MPP, fully antagonized E2 stimulation of pS2 mRNA in MCF-7 breast cancer cells, consistent with the fact that these cells contain almost exclusively ER(alpha). These compounds should be useful in studying the biological functions of ER(alpha) and ER(beta) and in selectively blocking responses that are mediated through ER(alpha).

Importance Elevated levels of cardiac troponins are associated with adverse clinical outcomes among patients with heart failure (HF) and reduced ejection fraction. However, the clinical significance of troponin elevation in the setting of decompensated HF with preserved ejection fraction (HFpEF) is not well established. Objective To determine the clinical predictors of troponin elevation and its association with in-hospital and long-term outcomes among patients with decompensated HFpEF. Design, Setting, and Participants Observational analysis of Get With The Guidelines–HF registry participants who were admitted for decompensated HFpEF (ejection fraction ≥50%) from January 2009 through December 2014 and who had quantitative or categorical (elevated vs normal based on institution’s reference laboratory) measures of troponin level (troponin T or troponin I, as available). Main Outcomes and Measures In-hospital outcomes (mortality, length of stay, and discharge destination) and postdischarge outcomes (30-day mortality, 30-day readmission rate, 1-year mortality). Results We included 34 233 patients with HFpEF from 224 sites with measured troponin levels (33.4% men; median age, 79 years): 78.6% (n = 26 896) with troponin I and 21.4% (n = 7319) with troponin T measurements. Among these, 22.6% (n = 7732) had elevation in troponin levels. In adjusted analysis, higher serum creatinine level, black race, older age, and ischemic heart disease were associated with troponin elevation. Elevated troponin was associated with higher odds of in-hospital mortality (odds ratio [OR], 2.19; 95% CI, 1.88-2.56), greater length of stay (length of stay >4 days OR, 1.38; 95% CI, 1.29-1.47), and lower likelihood of discharge to home (OR, 0.65; 95% CI, 0.61-0.71) independent of other clinical predictors and measured confounders. Presence of elevated troponin I levels was also significantly associated with increased risk of 30-day mortality (hazard ratio [HR], 1.59; 95% CI, 1.42-1.80), 30-day all-cause readmission (HR, 1.12; 95% CI, 1.01-1.25), and 1-year mortality HR, 1.35; 95% CI, 1.26-1.45). Conclusions and Relevance Troponin elevation among patients with acutely decompensated HFpEF is associated with worse in-hospital and postdischarge outcomes, independent of other predictive variables. Future studies are needed to determine if measurement of troponin levels among patients with decompensated HFpEF may be useful for risk stratification.

Background: In Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE), apixaban (vs. warfarin) significantly reduced stroke, death, and major bleeding in 18,201 patients with atrial fibrillation (AF). We assessed the cost-effectiveness of apixaban vs. warfarin from the perspective of the US health care system. Methods: Resource use (service dates, intensive care days, days on drug) was obtained from ARISTOTLE case report forms. Unit costs for components of hospital-based care of AF patients were estimated with generalized linear models using the national Premier database. Daily cost of anticoagulants was based on current acquisition cost (apixaban=$9.49; warfarin=$0.09) for 10 years, after which time apixaban was valued at projected costs of generic substitutes ($1.89). Physician services and anticoagulant monitoring were valued using Medicare fees. Within-trial costs were estimated using inverse probability weighting for differential follow-up. Survival was modeled with patient-level ARISTOTLE data using a two stage approach that combined a time-based Cox model for the within-trial period and an age-based Cox model for extrapolation. Uncertainty surrounding estimates of cost, life expectancy and cost/per life year gained was characterized with bootstraps and sensitivity analyses. Results: After 2 years, costs in the US cohort (n=3417) excluding study drug and monitoring averaged $306 less with apixaban than warfarin ($6257 vs. $6563). This difference was more than offset by higher apixaban anticoagulation costs ($6160 vs. $1181), resulting in an overall increase of $4673/patient. Over a lifetime, gains in life expectancy with apixaban (9.92 vs. 9.69; p Conclusions: Reductions in mortality, stroke, and bleeding observed in ARISTOTLE translate to significant increases in life expectancy. At an estimated ICER of $76,365/life year gained, apixaban is a cost-effective alternative to warfarin.