Spatial PD-L1, immune-cell microenvironment, and genomic copy-number alteration patterns and drivers of invasive-disease transition in prospective oral precancer cohort.

BACKGROUND: Studies of the immune landscape led to breakthrough trials of programmed death-1 (PD-1) inhibitors for recurrent/metastatic head and neck squamous cell carcinoma therapy. This study investigated the timing, influence of somatic copy-number alterations (SCNAs), and clinical implications of PD-L1 and immune-cell patterns in oral precancer (OPC). METHODS: The authors evaluated spatial CD3, CD3/8, and CD68 density (cells/mm2 ) and PD-L1 (membranous expression in cytokeratin-positive intraepithelial neoplastic cells and CD68) patterns by multiplex immunofluorescence in a 188-patient prospective OPC cohort, characterized by clinical, histologic, and SCNA risk factors and protocol-specified primary end point of invasive cancer. The authors used Wilcoxon rank-sum and Fisher exact tests, linear mixed effect models, mediation, and Cox regression and recursive-partitioning analyses. RESULTS: Epithelial, but not CD68 immune-cell, PD-L1 expression was detected in 28% of OPCs, correlated with immune-cell infiltration, 9p21.3 loss of heterozygosity (LOH), and inferior oral cancer-free survival (OCFS), notably in OPCs with low CD3/8 cell density, dysplasia, and/or 9p21.3 LOH. High CD3/8 cell density in dysplastic lesions predicted better OCFS and eliminated the excess risk associated with prior oral cancer and dysplasia. PD-L1 and CD3/8 patterns revealed inferior OCFS in PD-L1 high intrinsic induction and dysplastic immune-cold subgroups. CONCLUSION: This report provides spatial insight into the immune landscape and drivers of OPCs, and a publicly available immunogenomic data set for future precancer interrogation. The data suggest that 9p21.3 LOH triggers an immune-hot inflammatory phenotype; whereas increased 9p deletion size encompassing CD274 at 9p24.1 may contribute to CD3/8 and PD-L1 depletion during invasive transition. The inferior OCFS in PD-L1-high, immune-cold OPCs support the development of T-cell recruitment strategies.

Bayesian clinical trials at The University of Texas MD Anderson Cancer Center: An update.

BACKGROUND/AIMS: In our 2009 article, we showed that Bayesian methods had established a foothold in developing therapies in our institutional oncology trials. In this article, we will document what has happened since that time. In addition, we will describe barriers to implementing Bayesian clinical trials, as well as our experience overcoming them. METHODS: We reviewed MD Anderson Cancer Center clinical trials submitted to the institutional protocol office for scientific and ethical review between January 2009 and December 2013, the same length time period as the previous article. We tabulated Bayesian methods implemented for design or analyses for each trial and then compared these to our previous findings. RESULTS: Overall, we identified 1020 trials and found that 283 (28%) had Bayesian components so we designated them as Bayesian trials. Among MD Anderson-only and multicenter trials, 56% and 14%, respectively, were Bayesian, higher rates than our previous study. Bayesian trials were more common in phase I/II trials (34%) than in phase III/IV (6%) trials. Among Bayesian trials, the most commonly used features were for toxicity monitoring (65%), efficacy monitoring (36%), and dose finding (22%). The majority (86%) of Bayesian trials used non-informative priors. A total of 75 (27%) trials applied Bayesian methods for trial design and primary endpoint analysis. Among this latter group, the most commonly used methods were the Bayesian logistic regression model (N = 22), the continual reassessment method (N = 20), and adaptive randomization (N = 16). Median institutional review board approval time from protocol submission was the same 1.4 months for Bayesian and non-Bayesian trials. Since the previous publication, the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial was the first large-scale decision trial combining multiple treatments in a single trial. Since then, two regimens in breast cancer therapy have been identified and published from the cooperative Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis (I-SPY 2), enhancing cooperation among investigators and drug developers across the nation, as well as advancing information needed for personalized medicine. Many software programs and Shiny applications for Bayesian trial design and calculations are available from our website which has had more than 21,000 downloads worldwide since 2004. CONCLUSION: Bayesian trials have the increased flexibility in trial design needed for personalized medicine, resulting in more cooperation among researchers working to fight against cancer. Some disadvantages of Bayesian trials remain, but new methods and software are available to improve their function and incorporation into cancer clinical research.

Rates of Positive Findings on Positron Emission Tomography and Bone Marrow Biopsy in Patients With Ocular Adnexal Lymphoma.

PURPOSE: The aim of this study was to determine rates of positive findings on positron emission tomography (PET) and bone marrow biopsy performed during staging workup for ocular adnexal lymphoma (OAL). METHODS: A retrospective review of OAL patients was conducted. Demographics, primary versus secondary OAL, histologic subtype, and findings on PET and bone marrow biopsy performed as part of the initial staging workup for OAL were recorded. RESULTS: The study included 119 patients with OAL. There were 85 primary and 34 secondary OALs. The main histologic subtypes of lymphoma were mucosa-associated lymphoid tissue (n = 61), follicular (n = 26), diffuse large B-cell (n = 17), and mantle cell (n = 10). Positive PET findings were seen in 42 of 68 patients (62%) with primary OAL and 19 of 24 (79%) with secondary OAL. Positive PET findings were seen in 24 of 47 patients (51%) with mucosa-associated lymphoid tissue, 13 of 17 (76%) with follicular, 14 of 15 (93%) with diffuse large B-cell, and 9 of 10 (90%) with mantle cell lymphoma. Positive findings on bone marrow biopsy were seen in 7 of 59 patients (12%) with mucosa-associated lymphoid tissue, 4 of 23 (17%) with follicular, 1 of 17 (6%) with diffuse large B-cell, and 2 of 9 (22%) with mantle cell lymphoma. CONCLUSIONS: Our findings suggest that a significant proportion of patients with primary and secondary OAL have positive findings on PET and bone marrow biopsy at initial diagnosis, suggesting a reasonable yield for these tests as part of the initial staging workup in patients with a new diagnosis of OAL.

Association of early physician follow-up and 30-day readmission after non-ST-segment-elevation myocardial infarction among older patients.

BACKGROUND: Hospital readmission rates within 30 days after acute myocardial infarction are a national performance metric. Previous data suggest that early physician follow-up after heart failure hospitalizations can reduce readmissions; whether these results can be extended to acute myocardial infarction is unclear. METHODS AND RESULTS: We analyzed data from the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines (CRUSADE) Registry linked with Medicare claims from 2003 to 2006 for 25 872 non-ST-segment-elevation myocardial infarction patients ≥65 years of age discharged home from 228 hospitals with >25 patients and full revascularization capabilities. After adjusting for patient, treatment, and hospital characteristics, we examined the relationship between hospital-level physician follow-up within 7 days of discharge and 30-day all-cause readmission using logistic regression. The median hospital-level percentage of patients receiving early physician follow-up was 23.3% (interquartile range, 17.1%-29.1%). Among 24 165 patients with Medicare fee-for-service eligibility 30 days after discharge, 18.5% of patients were readmitted within 30 days of index hospitalization. Unadjusted and adjusted rates of 30-day readmission did not differ among quartiles of hospital-level early physician follow-up. Similarly, each 5% increase in hospital early follow-up was associated with an insignificant change in risk for readmission (adjusted odds ratio, 0.99; 95% confidence interval, 0.97-1.02; P=0.60). Sensitivity analyses extended these null findings to 30-day cardiovascular readmissions, high-risk subgroups, and early cardiology follow-up. CONCLUSIONS: Although rates of early physician follow-up after acute myocardial infarction varied among US hospitals, hospitals with higher early follow-up rates did not have lower 30-day readmission rates. Targeting strategies other than early physician follow-up may be necessary to reduce readmissions in this population.

Emergency department bypass for ST-Segment-elevation myocardial infarction patients identified with a prehospital electrocardiogram: a report from the American Heart Association Mission: Lifeline program.

BACKGROUND: For patients identified before hospital arrival with ST-segment-elevation myocardial infarction, bypassing the emergency department (ED) with direct transport to the catheterization laboratory may shorten reperfusion times. METHODS AND RESULTS: We studied 12 581 ST-segment-elevation myocardial infarction patients identified with a prehospital ECG treated at 371 primary percutaneous coronary intervention-capable US hospitals participating in the Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With The Guidelines, including those participating in the American Heart Association Mission: Lifeline program from 2008 to 2011. Reperfusion times with primary percutaneous coronary intervention and in-hospital mortality rates were compared between patients undergoing ED evaluation and those bypassing the ED. ED bypass occurred in 1316 patients (10.5%). These patients had a lower frequency of heart failure and shock on presentation and nonsystem reasons for delay in percutaneous coronary intervention. ED bypass occurred more frequently during working hours compared with off-hours (18.3% versus 4.3%); ED bypass rate varied significantly across hospitals (median, 3.3%; range, 0%-71%). First medical contact to device activation time was shorter (median, 68 minutes [interquartile range, 54-85 minutes] versus 88 minutes [interquartile range, 73-106 minutes]; P<0.0001) and achieved within 90 minutes more frequently (80.7% versus 53.7%; P<0.0001) with ED bypass. The unadjusted in-hospital mortality rate was lower among ED bypass patients (2.7% versus 4.1%; P=0.01), but the adjusted mortality risk was similar (adjusted odds ratio, 0.69; 95% confidence interval, 0.45-1.03; P=0.07). CONCLUSIONS: Among ST-segment-elevation myocardial infarction patients identified with a prehospital ECG, the rate of ED bypass varied significantly across US hospitals, but ED bypass occurred infrequently and was mostly isolated to working hours. Because ED bypass was associated with shorter reperfusion times and numerically lower mortality rates, further exploration of and advocacy for the implementation of this process appear warranted.

Association between prehospital electrocardiogram use and patient home distance from the percutaneous coronary intervention center on total reperfusion time in ST-segment-elevation myocardial infarction patients: a retrospective analysis from the national cardiovascular data registry.

BACKGROUND: Current guidelines recommend ≤90 minutes from first medical contact to percutaneous coronary intervention (FMC2B) for ST-segment-elevation myocardial infarction (STEMI) patients. We evaluated the relationship between patient home distance from a percutaneous coronary intervention (PCI) center, prehospital electrocardiogram (ECG) use, and FMC2B time among patients with STEMI. METHODS: We performed a retrospective cohort study including all STEMI patients in the ACTION-Get With The Guidelines registry from July 1, 2008, to September 30, 2012, who were transported by ambulance to a PCI center. Patient home distance was defined as the driving distance from the patient's home zip code to the PCI center address. Distance was classified into tertiles, and linear regression was used to characterize the interaction between prehospital ECG use and patient home distance with respect to FMC2B time. RESULTS: Of the 29,506 STEMI patients, 19,690 (67%) received a prehospital ECG. The median patient home distance to the PCI center was 11.0 miles among patients with and 9.9 miles among those without a prehospital ECG. Prehospital ECGs were associated with a 10-minute reduction in the FMC2B time (P < .0001), which was consistent across distance tertiles (11 vs 11 vs 10 minutes). The association between prehospital ECGs and shorter FMC2B was attenuated by 0.8 minute for every 10-mile increase in distance (interaction P = .0002). CONCLUSIONS: Prehospital ECGs are associated with a 10-minute reduction in the FMC2B time. However, patient home distance from a PCI center does not substantially change this association.

Association of chronic lung disease with treatments and outcomes patients with acute myocardial infarction.

BACKGROUND: Although chronic lung disease (CLD) is common among patients with myocardial infarction (MI), little is known about the influence of CLD on patient management and outcomes following MI. METHODS: Using the National Cardiovascular Data Registry's ACTION Registry-GWTG, demographics, clinical characteristics, treatments, processes of care, and in-hospital adverse events after acute MI were compared between patients with (n = 22,624) and without (n = 136,266) CLD. Multivariable adjustment was performed to determine the independent association of CLD with treatments and adverse events. RESULTS: CLD (17.0% of non-ST-elevation MI [NSTEMI] and 10.1% of ST-elevation MI [STEMI] patients) was associated with older age, female sex, and a greater burden of comorbidities. Among NSTEMI patients, those with CLD were less likely to undergo cardiac catheterization, percutaneous coronary intervention, and coronary artery bypass graft compared to those without; in contrast, no differences were seen in invasive therapies for STEMI patients with or without CLD. Multivariable-adjusted risk of major bleeding was significantly increased in CLD patients with NSTEMI (13.0% vs 8.1%, OR(adj) = 1.27, 95% CI = 1.20-1.34, P < .001) and STEMI (16.0% vs 10.5%, OR(adj) = 1.19, 95% CI = 1.10-1.29, P < .001). In NSTEMI, CLD was associated with a higher risk of inhospital mortality (OR(adj) = 1.21, 95% CI = 1.11-1.33); in STEMI no association between CLD and mortality was seen (OR(adj) = 1.05, 95% CI = 0.95-1.17). CONCLUSIONS: CLD is common among patients with MI and is independently associated with an increased risk for major bleeding. In NSTEMI, CLD is also associated with receiving less revascularization and with increased in-hospital mortality. Special attention should be given to this high-risk subgroup for the prevention and management of complications after MI.

Improving Care of STEMI in the United States 2008 to 2012.

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<0.001 over 5 years). Rates of cardiogenic shock and cardiac arrest, and overall in-hospital mortality increased (5.7% to 6.3%). Adjusted mortality excluding patients with known cardiac arrest decreased by 14% at 3 years and 25% at 5 years ( P<0.001). Conclusions Quality of care for patients with ST -segment-elevation myocardial infarction improved over time in Mission: Lifeline, including increased use of reperfusion therapy and faster times-to-treatment. In-hospital mortality improved for patients without cardiac arrest but did not appear to improve overall as the number of these high-risk patients increased.

Smaller Diameter Anastomotic Coupling Devices Have Higher Rates of Venous Thrombosis in Microvascular Free Tissue Transfer.

BACKGROUND: Smaller anastomotic coupling devices may increase the risk of complications in free flap reconstructions; however, the relationship between coupler size and venous thrombosis rates has not been adequately evaluated. The authors hypothesized that smaller diameter coupling devices are associated with higher rates of venous thrombosis than larger diameter devices in free tissue transfer. METHODS: The authors reviewed a prospectively maintained database for all patients who underwent microsurgical free tissue transfer at their institution from 2001 to 2013. The primary outcome measured was venous thrombosis, and the primary objective was to assess the relationship between venous coupler diameter and the rate of venous thrombosis. The secondary objective was to compare venous thrombosis rates between coupled and hand-sewn venous anastomoses. RESULTS: A total of 5643 consecutive free flap reconstructions were evaluated; 3257 (57.7 percent) had coupled venous anastomoses. The 1.5-mm-diameter coupler had an overall thrombosis rate of 6.9 percent, significantly higher than that of all other coupler sizes (p = 0.04). In multivariable regression with generalized estimating equations analysis, both use of a 1.5-mm coupler (OR, 7.75; 95 percent CI, 3.20 to 18.76; p < 0.0001) and preoperative radiation therapy (OR, 1.62; 95 percent CI, 1.04 to 2.52; p = 0.03) were significant independent predictors of venous thrombosis. CONCLUSIONS: The authors found a significantly higher rate of venous thrombosis with the 1.5-mm-diameter coupler than with larger diameter devices or hand-sewn venous anastomoses. This evidence suggests that surgeons should choose an outflow vessel that does not require a coupler diameter smaller than 2.0 mm or perform a hand-sewn anastomosis in situations where this is not possible. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Racial Differences in 20-Year Cardiovascular Mortality Risk Among Childhood and Young Adult Cancer Survivors.

PURPOSE: Whether cardiovascular disease (CVD) risk differs according to race and cancer type among survivors of childhood or young adulthood cancers is unknown. METHODS: Data from the years 1973-2011 were analyzed using the Surveillance, Epidemiology, and End Results (SEER) registries. Cases were categorized by ICD-0-3/WHO 2008 Adolescent and Young Adult classification. CVD death was determined by ICD-10 codes for diseases of the heart, atherosclerosis, cerebrovascular diseases, or other diseases of the arteries. Cox proportional hazards models were fitted to evaluate the hazard ratio (HR) and 95% confidence intervals (CIs) for the effects of race on time-to-event outcomes. RESULTS: A total of 164,316 cases of childhood and young adult primary cancers were identified. There were 43,335 total and 1466 CVD deaths among Black and White survivors. Black survivors had higher risks of all-cause mortality (HR: 1.75, 95% CI: 1.70-1.7) and CVD mortality (HR: 2.13, 95% CI: 1.85-2.46) compared to White survivors. The increased risk of CVD for Black survivors compared to White survivors persisted at 5-years (HR: 2.38, 95% CI: 1.83-3.10), 10-years (HR: 2.59, 95% CI: 2.09-3.21), and 20-years (HR: 2.31, 95% CI: 1.95-2.74) postdiagnosis, and varied by cancer type, with the highest HRs for melanoma (HR: 8.16, 95% CI: 1.99-33.45) and thyroid cancer (HR: 3.43, 95% CI: 1.75-6.73). CONCLUSIONS: Black survivors of childhood or young adulthood cancers have a higher risk of CVD mortality compared to Whites that varies by cancer type. Knowledge of at-risk populations is important to guide surveillance recommendations and behavioral interventions. Further study is needed to understand the etiology of racial differences in CVD mortality in this population.

Response rates to single-agent chemotherapy after exposure to immune checkpoint inhibitors in advanced non-small cell lung cancer.

INTRODUCTION: Exploratory analysis of clinical trials in various tumor types have demonstrated potential improvements in overall response rate (ORR) to chemotherapy after exposure to vaccine-based immunotherapy. The objective of this retrospective study was to determine if single-agent chemotherapy (3rd-line or beyond) would yield improved ORR when given after exposure to programmed death-(ligand)1 inhibitors (anti-PD1) in metastatic non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: We queried the Thoracic GEMINI database of MD Anderson Cancer Center for patients treated between 06/12 and 11/16 who received at least one single-agent chemotherapy as 3rd-line or beyond, following progression after platinum-based chemotherapy and anti-PD1. We evaluated efficacy outcomes to each therapy, including ORR by RECIST version 1.1, progression-free survival (PFS), and overall survival (OS). RESULTS: Out of 306 anti-PD1-treated patients registered in the database, 28 met eligibility criteria - 54% were male, median age was 66 years, 82% had adenocarcinoma, and 71% were former/current smokers. The anti-PD1 and single-agent chemotherapy most commonly used were nivolumab (86%) and docetaxel (50%), respectively. ORR to single-agent chemotherapy after exposure to anti-PD1 was 39% (11/28 patients, 8 confirmed). In contrast, ORR to first-line chemotherapy in this cohort was 37%. Liver metastasis was the only factor associated with response to single-agent chemotherapy on univariate analysis (p<0.05). CONCLUSION: In NSCLC patients, the confirmed ORR to single-agent chemotherapy after immunotherapy exposure was higher as compared to historical data from the pre-anti-PD1 era, and approached ORR to first-line platinum-based chemotherapy. Further investigation of a possible immunotherapy-induced chemosensitization effect is warranted.

Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration in the Nodal Staging of Stereotactic Ablative Body Radiotherapy Patients.

BACKGROUND: Patients with non-small cell lung cancer (NSCLC) being evaluated for stereotactic ablative body radiotherapy (SABR) are typically staged noninvasively with positron emission tomography/computed tomography (PET/CT). Incorporating endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) into the staging workup of these patients has not been evaluated. Our primary objective was to compare the performance of PET/CT with EBUS-TBNA for intrathoracic nodal assessment among SABR-eligible patients. METHODS: This was a retrospective study consisting of two parts. First, we assessed the concordance for nodal metastasis of PET/CT and EBUS-TBNA. Second, we evaluated clinical outcomes among patients who underwent SABR with and without a prior EBUS-TBNA. RESULTS: We identified 246 eligible patients. Compared with PET/CT, EBUS-TBNA led to a stage shift in 48 of 246 patients (19%). Of 174 N0 patients by PET/CT, 6 (3.4%) had nodal metastasis on EBUS-TBNA. Among 72 clinical N1 patients, 36 (50%) were downstaged to N0 after EBUS-TBNA, therefore becoming eligible for SABR. Concordance between PET/CT and EBUS-TBNA for nodal metastasis was 83% (κ = 0.53). Clinical outcomes of patients who underwent SABR with or without a prior EBUS-TBNA did not differ significantly. CONCLUSIONS: Concordance of PET/CT and EBUS-TBNA for nodal disease was only moderate. Incorporating EBUS-TBNA into the staging workup was beneficial in identifying occult nodal metastasis that would otherwise be left untreated with SABR and in expanding the pool of potentially SABR-eligible patients.

Outcomes According to Cardiac Catheterization Referral and Clopidogrel Use Among Medicare Patients With Non-ST-Segment Elevation Myocardial Infarction Discharged Without In-hospital Revascularization.

BACKGROUND: While use of P2Y12 receptor inhibitor is recommended by guidelines, few studies have examined its effectiveness among older non-ST-segment elevation myocardial infarction patients who did not undergo coronary revascularization. METHODS AND RESULTS: We included unrevascularized non-ST-segment elevation myocardial infarction patients ≥65 years discharged home from 463 ACTION Registry-GWTG hospitals from 2007 to 2010. Rates of discharge clopidogrel use were described for patients with no angiography, angiography without obstructive coronary artery disease (CAD; ≥50% stenosis in ≥1 vessel), and angiography with obstructive CAD. Two-year outcomes were ascertained from linked Medicare data and included composite major adverse cardiac events (defined as all-cause death, myocardial infarction readmission, or revascularization), and individual components. Outcomes associated with clopidogrel use were adjusted using inverse probability-weighted propensity modeling. Of 14 154 unrevascularized patients, 54.7% (n=7745) did not undergo angiography, 10.6% (n=1494) had angiography without CAD, and 34.7% (n=4915) had angiography with CAD. Discharge clopidogrel was prescribed for 42.2% of all unrevascularized patients: 37.8% without angiography, 34.1% without obstructive CAD at angiography, and 51.6% with obstructive CAD at angiography. Discharge clopidogrel use was not associated with major adverse cardiac events in any group: without angiography (adjusted hazard ratio [95% CI]: 0.99 [0.93-1.06]), angiography without CAD (1.04 [0.74-1.47]), and angiography with CAD (1.12 [1.00-1.25], Pinteraction=0.20). CONCLUSIONS: We found no association between discharge clopidogrel use and long-term risk of major adverse cardiac events among older, unrevascularized non-ST-segment elevation myocardial infarction patients. Clopidogrel use in this population requires further prospective evaluation.

Effectiveness and Safety of Aldosterone Antagonist Therapy Use Among Older Patients With Reduced Ejection Fraction After Acute Myocardial Infarction.

BACKGROUND: While aldosterone antagonists have proven benefit among post-myocardial infarction (MI) patients with low ejection fraction (EF), how this treatment is used among older MI patients in routine practice is not well described. METHODS AND RESULTS: Using ACTION Registry-GWTG linked to Medicare data, we examined 12 080 MI patients ≥65 years with EF ≤40% who were indicated for aldosterone antagonist therapy per current guidelines and without documented contraindications. Of these, 11% (n=1310) were prescribed aldosterone antagonists at discharge. Notably, 10% of patients prescribed an aldosterone antagonist were eligible for, but not concurrently treated with, an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker. Spironolactone was the predominantly prescribed aldosterone antagonist. At 2-year follow-up, aldosterone antagonist use was not associated with lower mortality (unadjusted 39% versus 38%; HR 0.99, 95% CI 0.88-1.33 using inverse probability-weighted propensity adjustment) except in symptomatic HF patients (HR 0.84, 95% CI 0.72-0.99, Pinteraction=0.009). Risks of hyperkalemia were low at 30 days, but significantly higher among patients prescribed aldosterone antagonists (unadjusted 2.3% versus 1.5%; adjusted HR 2.04, 95% CI 1.16-3.60), as was 2-year risk of acute renal failure (unadjusted 6.7% versus 4.8%; adjusted HR 1.39, 95% CI 1.01-1.92) compared with patients not prescribed aldosterone antagonists. CONCLUSIONS: Aldosterone antagonist use among eligible older MI patients in routine clinical practice was not associated with lower mortality except in patients with HF symptoms, but was associated with increased risks of hyperkalemia and acute renal failure. These results underscore the importance of close post-discharge monitoring of this patient population.

The BATTLE-2 Study: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients With Advanced Non-Small-Cell Lung Cancer.

PURPOSE: By applying the principles of real-time biopsy, biomarker-based, adaptively randomized studies in non-small-cell lung cancer (NSCLC) established by the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial, we conducted BATTLE-2 (BATTLE-2 Program: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients With Advanced Non-Small Cell Lung Cancer), an umbrella study to evaluate the effects of targeted therapies focusing on KRAS-mutated cancers. PATIENTS AND METHODS: Patients with advanced NSCLC (excluding sensitizing EGFR mutations and ALK gene fusions) refractory to more than one prior therapy were randomly assigned, stratified by KRAS status, to four arms: (1) erlotinib, (2) erlotinib plus MK-2206, (3) MK-2206 plus AZD6244, or (4) sorafenib. Tumor gene expression profiling-targeted next-generation sequencing was performed to evaluate predictive and prognostic biomarkers. RESULTS: Two hundred patients, 27% with KRAS-mutated (KRAS mut+) tumors, were adaptively randomly assigned to erlotinib (n = 22), erlotinib plus MK-2206 (n = 42), MK-2206 plus AZD6244 (n = 75), or sorafenib (n = 61). In all, 186 patients were evaluable, and the primary end point of an 8-week disease control rate (DCR) was 48% (arm 1, 32%; arm 2, 50%; arm 3, 53%; and arm 4, 46%). For KRAS mut+ patients, DCR was 20%, 25%, 62%, and 44% whereas for KRAS wild-type patients, DCR was 36%, 57%, 49%, and 47% for arms 1, 2, 3, and 4, respectively. Median progression-free survival was 2.0 months, not different by KRAS status, 1.8 months for arm 1, and 2.5 months for arms 2 versus arms 3 and 4 in KRAS mut+ patients (P = .04). Median overall survival was 6.5 months, 9.0 and 5.1 months for arms 1 and 2 versus arms 3 and 4 in KRAS wild-type patients (P = .03). Median overall survival was 7.5 months in mesenchymal versus 5 months in epithelial tumors (P = .02). CONCLUSION: Despite improved progression-free survival on therapy that did not contain erlotinib for KRAS mut+ patients and improved prognosis for mesenchymal tumors, better biomarker-driven treatment strategies are still needed.

Association of Patient Enrollment in Medicare Part D With Outcomes After Acute Myocardial Infarction.

BACKGROUND: Little is known about whether enrollment versus nonenrollment in Medicare's prescription drug plan (Part D) is associated with better outcomes after acute myocardial infarction (AMI). METHODS AND RESULTS: Using Medicare records linked to Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With The Guidelines, we identified 59 149 Medicare beneficiaries (age ≥65 years) discharged after AMI between January 2007 and December 2010. We described trends in Medicare Part D enrollment, and compared the following 30-day and 1-year outcomes: all-cause death, all-cause readmissions, and major adverse cardiac events (a composite of all-cause death or readmission for AMI or stroke) between Part D enrollees and nonenrollees, after adjustment for patient and hospital factors. From 2007 to 2010, 29 264 (49.5%) patients with AMI enrolled in Medicare were also participating in Part D by hospital discharge. All-cause 30-day death was more common among enrollees versus nonenrollees (4.0% versus 3.3%), but this difference was not statistically significant after multivariable adjustment (adjusted hazard ratio, 1.06 [95% confidence interval, 0.97-1.17]). Enrollees also had higher unadjusted risks of 30-day all-cause readmissions or major adverse cardiac events, and 1-year mortality, all-cause readmissions, or major adverse cardiac events, but these were attenuated after multivariable adjustment. Adherence to key secondary prevention medications (statins, ß-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and P2Y12 antagonists) remained low (range, 55%-64%) at 1 year post discharge among Part D enrollees. CONCLUSIONS: Only half of Medicare-insured patients with AMI were enrolled in Part D by hospital discharge, and their 30-day and 1-year adjusted outcomes did not differ substantially from nonenrollees. There remain opportunities for improvement in medication adherence among patients with prescription drug coverage.

Direct Transfer From the Referring Hospitals to the Catheterization Laboratory to Minimize Reperfusion Delays for Primary Percutaneous Coronary Intervention: Insights From the National Cardiovascular Data Registry.

BACKGROUND: For patients with ST-segment-elevation myocardial infarction (STEMI) requiring interhospital transfer for primary percutaneous coronary intervention, direct transfer from the STEMI referral hospital to the catheterization laboratory (cath lab) at the STEMI receiving hospital may expedite reperfusion, but can be logistically challenging. METHODS AND RESULTS: We studied 33,901 STEMI patients transferred for primary percutaneous coronary intervention in the Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With The Guidelines from July 2008 to December 2012. The majority of patients were transferred directly to the cath lab (26,510 [78.2%]), and 7391 patients (21.8%) were transferred first to the hospital emergency department/ward. We observed significant interhospital variation in transfer patterns; only 21% of STEMI receiving hospitals routinely transferred >90% of STEMI patients to the cath lab directly. Compared with patients transferred first to the emergency department/ward, STEMI patients transferred to the cath lab had significantly lower first door-to-balloon times (median 191 versus 116 minutes, P<0.0001). After multivariable logistic regression, patients transferred directly to the cath lab also had lower adjusted mortality risk (odds ratio 0.58, 95% confidence interval 0.51-0.66, P<0.0001). Cardiogenic shock, heart failure signs/symptoms, and nonsystem reasons for reperfusion delay were present in 11%, 15%, and 28% of patients transferred first to the emergency department/ward, respectively. The association of direct cath lab transfer with lower mortality persisted after excluding patients with these reasons for delay to primary percutaneous coronary intervention (adjusted odds ratio 0.62, 95% confidence interval 0.46-0.84, P=0.002). CONCLUSIONS: Direct transfer of STEMI patients to the cath lab for primary percutaneous coronary intervention was associated with significantly faster reperfusion and lower mortality risk compared with transfer first to the emergency department/ward.

Use and Outcomes of Triple Therapy Among Older Patients With Acute Myocardial Infarction and Atrial Fibrillation.

BACKGROUND: Antithrombotic therapy for acute myocardial infarction (MI) with atrial fibrillation (AF) among higher risk older patients treated with percutaneous coronary intervention (PCI) remains unclear. OBJECTIVES: This study sought to determine appropriate antithrombotic therapy for acute MI patients with AF treated with PCI. METHODS: We examined 4,959 patients ≥65 years of age with acute MI and AF who underwent coronary stenting (Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With the Guidelines). The primary effectiveness outcome was 2-year major adverse cardiac events (MACE) comprising death, readmission for MI, or stroke; the primary safety outcome was bleeding readmission. Outcomes with dual antiplatelet therapy (DAPT) or triple therapy (DAPT plus warfarin) were compared using Cox proportional hazard modeling with inverse probability-weighted propensity adjustment. RESULTS: Among 4,959 patients, 27.6% (n = 1,370) were discharged on triple therapy. Relative to DAPT, patients on triple therapy had a similar risk of MACE (adjusted hazard ratio [HR]: 0.99 [95% confidence interval (CI): 0.86 to 1.16]) but significantly greater risk of bleeding requiring hospitalization (adjusted HR: 1.61 [95% CI: 1.31 to 1.97]) and greater risk of intracranial hemorrhage (adjusted HR: 2.04 [95% CI: 1.25 to 3.34]). Of 1,591 Medicare Part D patients, 90-day post-discharge warfarin persistence among patients discharged on warfarin was 93.2% (n = 412). Results of 90-day landmark analyses comparing triple therapy versus DAPT in patients persistently on warfarin versus those not discharged on warfarin who had not filled a warfarin prescription were similar to our primary findings. CONCLUSIONS: Approximately 1 in 4 older AF patients undergoing PCI for MI were discharged on triple therapy. Those receiving triple therapy versus DAPT had higher rates of major bleeding without a measurable difference in composite MI, death, or stroke.

Association of body mass index and long-term outcomes in older patients with non-ST-segment-elevation myocardial infarction: results from the CRUSADE Registry.

BACKGROUND: Prior studies have found that obese patients have paradoxically lower in-hospital mortality after non-ST-segment-elevation myocardial infarction than their normal-weight counterparts, yet whether these associations persist long term is unknown. METHODS AND RESULTS: We linked detailed clinical data for patients with non-ST-segment-elevation myocardial infarction aged ≥65 years in the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the American College of Cardiology/American Heart Association Guidelines (CRUSADE) Registry to Medicare claims data to obtain longitudinal outcomes. Using height and weight measured on admission, patients were categorized into 6 body mass index (BMI [kilograms per meter squared]) groups. Multivariable Cox proportional hazards models were used to estimate the association between BMI and (1) all-cause mortality, (2) all-cause readmission, (3) cardiovascular readmission, and (4) noncardiovascular readmission for 3 years after hospital discharge. Among older patients with non-ST-segment-elevation myocardial infarction (n=34,465), 36.3% were overweight and 27.7% were obese. Obese patients were younger and more likely to have hypertension, diabetes mellitus, and dyslipidemia than normal or underweight patients. Relative to normal-weight patients, long-term mortality was lower for patients classified as overweight (BMI, 25.0-29.9), obese class I (BMI, 30.0-34.9), and obese class II (BMI, 35.0-39.9), but not obese class III (BMI ≥40.0). In contrast, 3-year all-cause and cardiovascular readmission were similar across BMI categories. Relative to normal-weight patients, noncardiovascular readmissions were similar for obese class I but higher for obese class II and obese class III. CONCLUSIONS: All-cause long-term mortality was generally lower for overweight and obese older patients after non-ST-segment-elevation myocardial infarction relative to those with normal weight. Longitudinal readmissions were similar or higher with increasing BMI.