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Background: Lisinopril and losartan manufacturer labels recommend twice-daily dosing (BID) if once-daily (QDay) is insufficient to lower blood pressure (BP)., Methods and Results: Retrospective cohort study of patients taking QDay lisinopril and losartan who experienced a dose-doubling (index date). A text-processing tool categorized BID and QDay groups at the index date based on administration instructions. We excluded: pregnant/hospice, regimens other than BID/QDay, and without BP measurements -6 months/+12 months of the index date. The most proximal BP measurements -6 months and +2 weeks to 12 months of the index date were used to evaluate BP differences. Propensity scores were generated, and differences in BP and adverse events (angioedema, acute kidney injury, hyperkalemia) between BID/QDay groups were analyzed within dosing cohorts using inverse propensity of treatment-weighted regression models. Of 11,210 and 6,051 patients who met all criteria for lisinopril and losartan, 784 (7.0%) and 453 (7.5%) were taking BID, respectively. BID patients were older and had higher comorbidity and medication burdens. There were no differences in systolic/diastolic BP between BID and QDay, with absolute differences in mean systolic BP ranging from -1.8 to 0.7 mmHg and diastolic BP ranging from -1.1 to 0.1 mmHg (all 95% confidence intervals [CI] cross 0). Lisinopril 10mg BID was associated with an increased odds of angioedema compared to lisinopril 20mg QDay (odds ratio 2.27, 95%CI 1.13-4.58)., Conclusions: Adjusted models do not support improved effectiveness or safety of BID lisinopril and losartan., Competing Interests: The authors have declared that no competing interests exist.

Background: Elective percutaneous coronary interventions (PCI) are difficult to discriminate from non-elective PCI in administrative data due to non-specific encounter codes, limiting the ability to track outcomes, ensure appropriate medical management, and/or perform research on patients who undergo elective PCI. The objective of this study was to assess the abilities of several algorithms to identify elective PCI procedures using administrative data containing diagnostic, utilization, and/or procedural codes., Methods and Results: For this retrospective study, administrative databases in an integrated healthcare delivery system were queried between 1/1/2015 and 6/31/2016 to identify patients who had an encounter for a PCI. Using clinical criteria, each encounter was classified via chart review as a valid PCI, then as elective or non-elective. Cases were tested against nine pre-determined algorithms. Performance statistics (sensitivity, specificity, positive predictive value, and negative predictive value) and associated 95% confidence intervals (CI) were calculated. Of 521 PCI encounters reviewed, 497 were valid PCI, 93 of which were elective. An algorithm that excluded emergency room visit events had the highest sensitivity (97.9%, 95%CI 92.5%-99.7%) while an algorithm that included events occurring within 90 days of a cardiologist visit and coronary angiogram or stress test had the highest positive predictive value (62.2%, 95%CI 50.8%-72.7%)., Conclusions: Without an encounter code specific for elective PCI, an algorithm excluding procedures associated with an emergency room visit had the highest sensitivity to identify elective PCI. This offers a reasonable approach to identify elective PCI from administrative data., Competing Interests: The authors have declared that no competing interests exist.

Objectives: To investigate the biologic relevance of cross-platform concordant changes in gene expression in intact human failing/hypertrophied ventricular myocardium undergoing reverse remodeling., Background: Information is lacking on genes and networks involved in remodeled human LVs, and in the associated investigative best practices., Methods: We measured mRNA expression in ventricular septal endomyocardial biopsies from 47 idiopathic dilated cardiomyopathy patients, at baseline and after 3-12 months of β-blocker treatment to effect left ventricular (LV) reverse remodeling as measured by ejection fraction (LVEF). Cross-platform gene expression change concordance was investigated in reverse remodeling Responders (R) and Nonresponders (NR) using 3 platforms (RT-qPCR, microarray, and RNA-Seq) and two cohorts (All 47 subjects (A-S) and a 12 patient "Super-Responder" (S-R) subset of A-S)., Results: For 50 prespecified candidate genes, in A-S mRNA expression 2 platform concordance (CcpT), but not single platform change, was directly related to reverse remodeling, indicating CcpT has biologic significance. Candidate genes yielded a CcpT (PCR/microarray) of 62% for Responder vs. Nonresponder (R/NR) change from baseline analysis in A-S, and ranged from 38% to 100% in S-R for PCR/microarray/RNA-Seq 2 platform comparisons. Global gene CcpT measured by microarray/RNA-Seq was less than for candidate genes, in S-R R/NR 17.5% vs. 38% (P = 0.036). For S-R global gene expression changes, both cross-cohort concordance (CccT) and CcpT yielded markedly greater values for an R/NR vs. an R-only analysis (by 22 fold for CccT and 7 fold for CcpT). Pathway analysis of concordant global changes for R/NR in S-R revealed signals for downregulation of multiple phosphoinositide canonical pathways, plus expected evidence of a β1-adrenergic receptor gene network including enhanced Ca2+ signaling., Conclusions: Two-platform concordant change in candidate gene expression is associated with LV biologic effects, and global expression concordant changes are best identified in an R/NR design that can yield novel information., Competing Interests: This work was funded in part by industry sponsored research awards from GlaxoSmithKline, AstraZeneca and ARCA biopharma (awarded to MRB). The industry funding was unrestricted and without any stipulations, other than receipt of reports of the findings in the form of scientific presentations or manuscripts. MRB was but is no longer a consultant for GlaxoSmithKline, and MRB and IAC are fractional employees of ARCA biopharma. MRB is a founder, officer and director of ARCA biopharma, and none of the information in this manuscript is related to any intellectual property licensed to or being developed by ARCA as the study was conceived, executed and analyzed within MRB’s academic functions and responsibilities. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Marijuana use is increasing worldwide, and it is ever more likely that patients presenting with acute myocardial infarctions (AMI) will be marijuana users. However, little is known about the impact of marijuana use on short-term outcomes following AMI. Accordingly, we compared in-hospital outcomes of AMI patients with reported marijuana use to those with no reported marijuana use. We hypothesized that marijuana use would be associated with increased risk of adverse outcomes in AMI patients. Hospital records from 8 states between 1994-2013 were screened for patients with a diagnosis of AMI. Clinical profiles and outcomes in patients with reported use of marijuana were compared to patients without reported marijuana use. Short-term outcomes were defined as adverse events that occurred during hospitalization for an admitting diagnosis of AMI. The composite primary outcome included death, intraaortic balloon pump placement, (IABP), mechanical ventilation, cardiac arrest, and shock. In total, 3,854 of 1,273,897 AMI patients reported use of marijuana. The marijuana cohort was younger than (47.2 vs. 57.2, respectively) and had less coronary artery disease than the non-marijuana cohort. In multivariable analysis including age, race and common cardiac risk factors, there was no association between marijuana use and the primary outcome (p = 0.53), but marijuana users were more likely to be placed on mechanical ventilation (OR (odds ratio) 1.19, p = 0.004). Interestingly, marijuana-using patients were significantly less likely to die (OR 0.79, p = 0.016), experience shock (OR 0.74, p = 0.001), or require an IABP (OR 0.80, p = 0.03) post AMI than patients with no reported marijuana use. These results suggest that, contrary to our hypothesis, marijuana use was not associated with increased risk of adverse short-term outcomes following AMI. Furthermore, marijuana use was associated with decreased in-hospital mortality post-AMI., Competing Interests: The authors have declared that no competing interests exist.

Background: Heart failure patients with reduced ejection fraction (HFREF) are heterogenous, and our ability to identify patients likely to respond to therapy is limited. We present a method of identifying disease subtypes using high-dimensional clinical phenotyping and latent class analysis that may be useful in personalizing prognosis and treatment in HFREF., Methods: A total of 1121 patients with nonischemic HFREF from the β-blocker Evaluation of Survival Trial were categorized according to 27 clinical features. Latent class analysis was used to generate two latent class models, LCM A and B, to identify HFREF subtypes. LCM A consisted of features associated with HF pathogenesis, whereas LCM B consisted of markers of HF progression and severity. The Seattle Heart Failure Model (SHFM) Score was also calculated for all patients. Mortality, improvement in left ventricular ejection fraction (LVEF) defined as an increase in LVEF ≥5% and a final LVEF of 35% after 12 months, and effect of bucindolol on both outcomes were compared across HFREF subtypes. Performance of models that included a combination of LCM subtypes and SHFM scores towards predicting mortality and LVEF response was estimated and subsequently validated using leave-one-out cross-validation and data from the Multicenter Oral Carvedilol Heart Failure Assessment Trial., Results: A total of 6 subtypes were identified using LCM A and 5 subtypes using LCM B. Several subtypes resembled familiar clinical phenotypes. Prognosis, improvement in LVEF, and the effect of bucindolol treatment differed significantly between subtypes. Prediction improved with addition of both latent class models to SHFM for both 1-year mortality and LVEF response outcomes., Conclusions: The combination of high-dimensional phenotyping and latent class analysis identifies subtypes of HFREF with implications for prognosis and response to specific therapies that may provide insight into mechanisms of disease. These subtypes may facilitate development of personalized treatment plans.