Device Therapies Among Patients Receiving Primary Prevention Implantable Cardioverter-Defibrillators in the Cardiovascular Research Network.

BACKGROUND: Primary prevention implantable cardioverter-defibrillators (ICDs) reduce mortality in selected patients with left ventricular systolic dysfunction by delivering therapies (antitachycardia pacing or shocks) to terminate potentially lethal arrhythmias; inappropriate therapies also occur. We assessed device therapies among adults receiving primary prevention ICDs in 7 healthcare systems. METHODS AND RESULTS: We linked medical record data, adjudicated device therapies, and the National Cardiovascular Data Registry ICD Registry. Survival analysis evaluated therapy probability and predictors after ICD implant from 2006 to 2009, with attention to Centers for Medicare and Medicaid Services Coverage With Evidence Development subgroups: left ventricular ejection fraction, 31% to 35%; nonischemic cardiomyopathy <9 months' duration; and New York Heart Association class IV heart failure with cardiac resynchronization therapy defibrillator. Among 2540 patients, 35% were <65 years old, 26% were women, and 59% were white. During 27 (median) months, 738 (29%) received ≥1 therapy. Three-year therapy risk was 36% (appropriate, 24%; inappropriate, 12%). Appropriate therapy was more common in men (adjusted hazard ratio [HR], 1.84; 95% confidence interval [CI], 1.43-2.35). Inappropriate therapy was more common in patients with atrial fibrillation (adjusted HR, 2.20; 95% CI, 1.68-2.87), but less common among patients ≥65 years old versus younger (adjusted HR, 0.72; 95% CI, 0.54-0.95) and in recent implants (eg, in 2009 versus 2006; adjusted HR, 0.66; 95% CI, 0.46-0.95). In Centers for Medicare and Medicaid Services Coverage With Evidence Development analysis, inappropriate therapy was less common with cardiac resynchronization therapy defibrillator versus single chamber (adjusted HR, 0.55; 95% CI, 0.36-0.84); therapy risk did not otherwise differ for Centers for Medicare and Medicaid Services Coverage With Evidence Development subgroups. CONCLUSIONS: In this community cohort of primary prevention patients receiving ICD, therapy delivery varied across demographic and clinical characteristics, but did not differ meaningfully for Centers for Medicare and Medicaid Services Coverage With Evidence Development subgroups.

Evaluation and Adaptation of a Laboratory-Based cDNA Library Preparation Protocol for Retrospective Sequencing of Archived MicroRNAs from up to 35-Year-Old Clinical FFPE Specimens.

Formalin-fixed paraffin-embedded (FFPE) specimens, when used in conjunction with patient clinical data history, represent an invaluable resource for molecular studies of cancer. Even though nucleic acids extracted from archived FFPE tissues are degraded, their molecular analysis has become possible. In this study, we optimized a laboratory-based next-generation sequencing barcoded cDNA library preparation protocol for analysis of small RNAs recovered from archived FFPE tissues. Using matched fresh and FFPE specimens, we evaluated the robustness and reproducibility of our optimized approach, as well as its applicability to archived clinical specimens stored for up to 35 years. We then evaluated this cDNA library preparation protocol by performing a miRNA expression analysis of archived breast ductal carcinoma in situ (DCIS) specimens, selected for their relation to the risk of subsequent breast cancer development and obtained from six different institutions. Our analyses identified six miRNAs (miR-29a, miR-221, miR-375, miR-184, miR-363, miR-455-5p) differentially expressed between DCIS lesions from women who subsequently developed an invasive breast cancer (cases) and women who did not develop invasive breast cancer within the same time interval (control). Our thorough evaluation and application of this laboratory-based miRNA sequencing analysis indicates that the preparation of small RNA cDNA libraries can reliably be performed on older, archived, clinically-classified specimens.

The Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) Screening Trial Pathology Tissue Resource.

BACKGROUND: Pathology tissue specimens with associated epidemiologic and clinical data are valuable for cancer research. The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial undertook a large-scale effort to create a public resource of pathology tissues from PLCO participants who developed a cancer during the trial. METHODS: Formalin-fixed paraffin-embedded tissue blocks were obtained from pathology laboratories on a loan basis for central processing of tissue microarrays, with additional free-standing tissue cores collected for nucleic acid extraction. RESULTS: Pathology tissue specimens were obtained for prostate cancer (n = 1,052), lung cancer (n = 434), colorectal cancer (n = 675) and adenoma (n = 658), ovarian cancer and borderline tumors (n = 212), breast cancer (n = 870), and bladder cancer (n = 204). The process of creating this resource was complex, involving multidisciplinary teams with expertise in pathology, epidemiology, information technology, project management, and specialized laboratories. CONCLUSIONS: Creating the PLCO tissue resource required a multistep process, including obtaining medical records and contacting pathology departments where pathology materials were stored after obtaining necessary patient consent and authorization. The potential to link tissue biomarkers to prospectively collected epidemiologic information, screening and clinical data, and matched blood or buccal samples offers valuable opportunities to study etiologic heterogeneity, mechanisms of carcinogenesis, and biomarkers for early detection and prognosis. IMPACT: The methods and protocols developed for this effort, and the detailed description of this resource provided here, will be useful for those seeking to use PLCO pathology tissue specimens for their research and may also inform future tissue collection efforts in other settings. Cancer Epidemiol Biomarkers Prev; 25(12); 1635-42. ©2016 AACR.

Longitudinal study of implantable cardioverter-defibrillators: methods and clinical characteristics of patients receiving implantable cardioverter-defibrillators for primary prevention in contemporary practice.

BACKGROUND: Implantable cardioverter-defibrillators (ICDs) are increasingly used for primary prevention after randomized, controlled trials demonstrating that they reduce the risk of death in patients with left ventricular systolic dysfunction. The extent to which the clinical characteristics and long-term outcomes of unselected, community-based patients with left ventricular systolic dysfunction undergoing primary prevention ICD implantation in a real-world setting compare with those enrolled in the randomized, controlled trials is not well characterized. This study is being conducted to address these questions. METHODS AND RESULTS: The study cohort includes consecutive patients undergoing primary prevention ICD placement between January 1, 2006 and December 31, 2009 in 7 health plans. Baseline clinical characteristics were acquired from the National Cardiovascular Data Registry ICD Registry. Longitudinal data collection is underway, and will include hospitalization, mortality, and resource use from standardized health plan data archives. Data regarding ICD therapies will be obtained through chart abstraction and adjudicated by a panel of experts in device therapy. Compared with the populations of primary prevention ICD therapy randomized, controlled trials, the cohort (n=2621) is on average significantly older (by 2.5-6.5 years), more often female, more often from racial and ethnic minority groups, and has a higher burden of coexisting conditions. The cohort is similar, however, to a national population undergoing primary prevention ICD placement. CONCLUSIONS: Patients undergoing primary prevention ICD implantation in this study differ from those enrolled in the randomized, controlled trials that established the efficacy of ICDs. Understanding a broad range of health outcomes, including ICD therapies, will provide patients, clinicians, and policy makers with contemporary data to inform decision-making.