Impact of CYP2C19 Metabolizer Status on Patients With ACS Treated With Prasugrel Versus Clopidogrel.

Background: Certain alleles of the CYP2C19 gene are associated with higher platelet reactivity and increased ischemic events among patients treated with clopidogrel. However, the relationship of CYP2C19 genotype and outcomes in medically managed patients with acute coronary syndromes (ACS) is not known.

Objectives: This study sought to assess the effect of CYP2C19 genotype on ischemic outcomes in patients with ACS initially managed medically without revascularization who were randomized to either clopidogrel or prasugrel.

Pharmacodynamics of Voriconazole in Children: Further Steps along the Path to True Individualized Therapy.

Voriconazole is the agent of choice for the treatment of invasive aspergillosis in children at least 2 years of age. The galactomannan index is a routinely used diagnostic marker for invasive aspergillosis and can be useful for following the clinical response to antifungal treatment. The aim of this study was to develop a pharmacokinetic-pharmacodynamic (PK-PD) mathematical model that links the pharmacokinetics of voriconazole with the galactomannan readout in children.

Accurately Achieving Target Busulfan Exposure in Children and Adolescents With Very Limited Sampling and the BestDose Software.

Background: Busulfan dose adjustment is routinely guided by plasma concentration monitoring using 4-9 blood samples per dose adjustment, but a pharmacometric Bayesian approach could reduce this sample burden.

Methods: The authors developed a nonparametric population model with Pmetrics. They used it to simulate optimal initial busulfan dosages, and in a blinded manner, they compared dosage adjustments using the model in the BestDose software to dosage adjustments calculated by noncompartmental estimation of area under the time-concentration curve at a national reference laboratory in a cohort of patients not included in model building.

An exploratory analysis of the ability of a cefepime trough concentration greater than 22 mg/L to predict neurotoxicity.

Introduction: Cefepime trough concentrations >22 mg/L (T(>22)) have been associated with neurotoxicity in a single study.

Patients And Methods: Neurotoxicity outcomes for 28 cefepime-treated adult patients with febrile neutropenia were abstracted from the literature. The precision of T(>22) to predict neurotoxicity was quantified using 95% confidence intervals.

Collaborative quality improvement vs public reporting for percutaneous coronary intervention: A comparison of percutaneous coronary intervention in New York vs Michigan.

Introduction: Public reporting (PR) is a policy mechanism that may improve clinical outcomes for percutaneous coronary intervention (PCI). However, prior studies have shown that PR may have an adverse impact on patient selection. It is unclear whether alternatives to PR, such as collaborative quality improvement (CQI), may drive improvements in quality of care and outcomes for patients receiving PCI without the unintended consequences seen with PR.

Defining Clinical Exposures of Cefepime for Gram-Negative Bloodstream Infections That Are Associated with Improved Survival.

The percentage of time that free drug concentrations remain above the MIC (fT>MIC) that is necessary to prevent mortality among cefepime-treated patients with Gram-negative bloodstream infections (GNBSI) is poorly defined. We conducted a retrospective study of adult patients with GNBSI. Eligible cases were frequency matched to ensure categorical representation from all MICs.

Recreating blood-brain barrier physiology and structure on chip: A novel neurovascular microfluidic bioreactor.

The blood-brain barrier (BBB) is a critical structure that serves as the gatekeeper between the central nervous system and the rest of the body. It is the responsibility of the BBB to facilitate the entry of required nutrients into the brain and to exclude potentially harmful compounds; however, this complex structure has remained difficult to model faithfully in vitro. Accurate in vitro models are necessary for understanding how the BBB forms and functions, as well as for evaluating drug and toxin penetration across the barrier.

Plasma and intracellular exposure to ganciclovir in adult renal transplant recipients: is there an association with haematological toxicity?

Objectives: Ganciclovir is the most widely used treatment for cytomegalovirus infections. However, neutropenia is a frequent associated adverse effect leading to a decrease in the ganciclovir dose or discontinuation of the therapy, thereby favouring viral resistance. In the present study, the objectives were: (i) to describe the pharmacokinetics of blood and intracellular ganciclovir and its metabolites; and (ii) to explore the relationship between exposure to ganciclovir and/or its metabolites and evolution of the neutrophil count under treatment.

Long-term outcomes for women versus men with unstable angina/non-ST-segment elevation myocardial infarction managed medically without revascularization: insights from the TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage Acute Coronary Syndromes trial.

Background: Women with acute coronary syndromes (ACS) are less likely to undergo invasive revascularization than men, but sex-specific differences in long-term outcomes and platelet reactivity among medically managed ACS patients remain uncertain. We examined sex-specific differences in long-term ischemic and bleeding outcomes and platelet reactivity for medically managed ACS patients randomized to prasugrel versus clopidogrel plus aspirin.

Methods: Data from 9,326 patients enrolled in TRILOGY ACS were analyzed to determine differences in long-term ischemic and bleeding outcomes between women (n = 3,650 [39%]) and men (n = 5,676 [61%]) randomized to prasugrel 10 mg/d (5 mg/d for patients ≥75 years and/or <60 kg) versus clopidogrel 75 mg/d.

Apixaban Plus Mono Versus Dual Antiplatelet Therapy in Acute Coronary Syndromes: Insights From the APPRAISE-2 Trial.

Background: Bleeding limits anticoagulant treatment in patients with acute coronary syndromes (ACS).

Objectives: We investigated whether background concomitant antiplatelet therapy influences the effects of apixaban after ACS.

Methods: This study examined high-risk ACS patients who were treated with aspirin or aspirin plus clopidogrel and who were randomized to apixaban 5 mg twice daily or placebo.

Impact of chronic kidney disease on long-term ischemic and bleeding outcomes in medically managed patients with acute coronary syndromes: Insights from the TRILOGY ACS Trial.

Aims: We aimed to study the relationship of chronic kidney disease stages with long-term ischemic and bleeding outcomes in medically managed acute coronary syndrome patients and the influence of more potent antiplatelet therapies on platelet reactivity by chronic kidney disease stage.

Methods And Results: We estimated creatinine clearance for 8953 medically managed acute coronary syndrome patients enrolled in the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes trial. Patients were classified by chronic kidney disease stage: normal renal function/mild (creatinine clearance >60 mL/min); moderate (creatinine clearance 30-60 mL/min); severe (creatinine clearance <30 mL/min).

Combinatorial polymer matrices enhance in vitro maturation of human induced pluripotent stem cell-derived cardiomyocytes.

Cardiomyocytes derived from human induced pluripotent stem cells (iPSC-CMs) hold great promise for modeling human heart diseases. However, iPSC-CMs studied to date resemble immature embryonic myocytes and therefore do not adequately recapitulate native adult cardiomyocyte phenotypes. Since extracellular matrix plays an essential role in heart development and maturation in vivo, we sought to develop a synthetic culture matrix that could enhance functional maturation of iPSC-CMs in vitro.

Characterising and predicting bleeding in high-risk patients with an acute coronary syndrome.

Objective: In the Apixaban for Prevention of Acute Ischemic Events (APPRAISE-2) trial, the use of apixaban, when compared with placebo, in high-risk patients with a recent acute coronary syndrome (ACS) resulted in a significant increase in bleeding without a reduction in ischaemic events. The aim of this analysis was to provide further description of these bleeding events and to determine the baseline characteristics associated with bleeding in high-risk post-ACS patients.

Methods: APPRAISE-2 was a multinational clinical trial including 7392 high-risk patients with a recent ACS randomised to apixaban (5 mg twice daily) or placebo.

Population modeling and simulation study of the pharmacokinetics and antituberculosis pharmacodynamics of isoniazid in lungs.

Among first-line antituberculosis drugs, isoniazid (INH) displays the greatest early bactericidal activity (EBA) and is key to reducing contagiousness in treated patients. The pulmonary pharmacokinetics and pharmacodynamics of INH have not been fully characterized with modeling and simulation approaches. INH concentrations measured in plasma, epithelial lining fluid, and alveolar cells for 89 patients, including fast acetylators (FAs) and slow acetylators (SAs), were modeled by use of population pharmacokinetic modeling.

Gaps in referral to cardiac rehabilitation of patients undergoing percutaneous coronary intervention in the United States.

Background: Rates of referral to cardiac rehabilitation after percutaneous coronary intervention (PCI) have been historically low despite the evidence that rehabilitation is associated with lower mortality in PCI patients.

Objectives: This study sought to determine the prevalence of and factors associated with referral to cardiac rehabilitation in a national PCI cohort, and to assess the association between insurance status and referral patterns.

Methods: Consecutive patients who underwent PCI and survived to hospital discharge in the National Cardiovascular Data Registry between July 1, 2009 and March 31, 2012 were analyzed.

Describing Assay Precision-Reciprocal of Variance Is Correct, Not CV Percent: Its Use Should Significantly Improve Laboratory Performance.

Background: Describing assay error as percent coefficient of variation (CV%) fails as measurements approach zero. Results are censored if below some arbitrarily chosen lower limit of quantification (LLOQ). CV% gives incorrect weighting to data obtained by therapeutic drug monitoring, with incorrect parameter values in the resulting pharmacokinetic models, and incorrect dosage regimens for patient care.

Lack of impact of electronic health records on quality of care and outcomes for ischemic stroke.

Background: Electronic health records (EHRs) may be key tools for improving the quality of health care, particularly for conditions for which guidelines are rapidly evolving and timely care is critical, such as ischemic stroke.

Objectives: The goal of this study was to determine whether hospitals with EHRs differed on quality or outcome measures for ischemic stroke from those without EHRs.

Methods: We studied 626,473 patients from 1,236 U.

Improved Tacrolimus Target Concentration Achievement Using Computerized Dosing in Renal Transplant Recipients--A Prospective, Randomized Study.

Background: Early after renal transplantation, it is often challenging to achieve and maintain tacrolimus concentrations within the target range. Computerized dose individualization using population pharmacokinetic models may be helpful. The objective of this study was to prospectively evaluate the target concentration achievement of tacrolimus using computerized dosing compared with conventional dosing performed by experienced transplant physicians.

Anticoagulant therapy and outcomes in patients with prior or acute heart failure and acute coronary syndromes: Insights from the APixaban for PRevention of Acute ISchemic Events 2 trial.

Background: Clinical outcomes and the effects of oral anticoagulants among patients with acute coronary syndrome (ACS) and either a history of or acute heart failure (HF) are largely unknown. We aimed to assess the relationship between prior HF or acute HF complicating an index ACS event and subsequent clinical outcomes and the efficacy and safety of apixaban compared with placebo in these populations.

Methods: High-risk patients were randomly assigned post-ACS to apixaban 5.

Optimal timing of oral fosfomycin administration for pre-prostate biopsy prophylaxis.

Objectives: As the optimal administration time for fosfomycin peri-procedural prophylaxis is unclear, we sought to determine optimal administration times for fosfomycin peri-procedural prophylaxis.

Methods: Plasma, peripheral zone and transition zone fosfomycin concentrations were obtained from 26 subjects undergoing transurethral resection of the prostate (TURP), following a single oral dose of 3 g of fosfomycin. Population pharmacokinetic modelling was completed with the Nonparametric Adaptive Grid (NPAG) algorithm (Pmetrics package for R), with a four-compartment model.

Achieving target voriconazole concentrations more accurately in children and adolescents.

Despite the documented benefit of voriconazole therapeutic drug monitoring, nonlinear pharmacokinetics make the timing of steady-state trough sampling and appropriate dose adjustments unpredictable by conventional methods. We developed a nonparametric population model with data from 141 previously richly sampled children and adults. We then used it in our multiple-model Bayesian adaptive control algorithm to predict measured concentrations and doses in a separate cohort of 33 pediatric patients aged 8 months to 17 years who were receiving voriconazole and enrolled in a pharmacokinetic study.