Spironolactone in Patients With Heart Failure, Preserved Ejection Fraction, and Worsening Renal Function.

Background: Treatment of heart failure with preserved ejection fraction (HFpEF) with spironolactone is associated with lower risk of heart failure hospitalization (HFH) but increased risk of worsening renal function (WRF). The prognostic implications of spironolactone-associated WRF in HFpEF patients are not well understood.

Objectives: The purpose of this study was to investigate the association between WRF, spironolactone treatment, and clinical outcomes in patients with HFpEF.

Comparison of Outcomes in Patients With Diabetes Mellitus Treated With Versus Without Insulin + Heart Failure With Preserved Left Ventricular Ejection Fraction (from the TOPCAT Study).

We aimed to evaluate the impact of diabetes mellitus (DM) and insulin treatment on clinical outcomes in patients with heart failure and preserved left ventricular ejection fraction enrolled in the TOPCAT study. We investigated the influence of DM status (insulin-treated [ITDM], non-insulin treated [NITDM], and no diabetes [non-DM]) at baseline on time to development of the primary end point, a composite of cardiovascular (CV) mortality, heart failure hospitalization, and aborted cardiac arrest. Secondary end points included the individual components of the primary end point, myocardial infarction, stroke, all-cause mortality, hyperkalemia, and worsened renal function.

Incident Hyperkalemia, Hypokalemia, and Clinical Outcomes During Spironolactone Treatment of Heart Failure With Preserved Ejection Fraction: Analysis of the TOPCAT Trial.

Background: In patients with heart failure and preserved ejection fraction (HF-PEF) randomized in the Americas as part of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial, treatment with spironolactone enhanced the risk of hyperkalemia but reduced the risk of hypokalemia. We examined the clinical correlates and prognostic implications of incident hypo- and hyperkalemia during study follow-up.

Methods: We defined the region-specific incidence of hypokalemia (potassium [K] <3.

Data and Safety Monitoring Board evaluation and management of a renal adverse event signal in TOPCAT.

Clinical trial Data and Safety Monitoring Boards (DSMBs) have a primary obligation of ensuring study participant safety, while maintaining trial integrity. The role of DSMBs is expanding, and ideally should include post-hoc reporting of deliberative processes related to clinically important safety issues or factors that could impact on future trial designs. We describe how the TOPCAT DSMB detected, investigated, and adjudicated an unexpectedly large renal adverse event signal midway through the trial, and offer general guidelines for dealing with similar unanticipated occurrences in future trials.

QRS Duration Is a Predictor of Adverse Outcomes in Heart Failure With Preserved Ejection Fraction.

Objectives: This study examined the relationship between baseline QRS duration and clinical outcomes in subjects enrolled in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial.

Background: Heart failure with preserved ejection fraction (HFPEF) is a heterogeneous clinical syndrome. Whether QRS duration identifies HFPEF subjects at an increased risk of adverse outcomes has not been well studied.

Influence of ejection fraction on outcomes and efficacy of spironolactone in patients with heart failure with preserved ejection fraction.

Aims: While mineralocorticoid receptor antagonists (MRAs) have been shown to benefit patients with reduced left ventricular ejection fraction (LVEF), spironolactone did not reduce the primary endpoint of cardiovascular death, heart failure hospitalization, or aborted cardiac arrest in patients with heart failure with preserved ejection fraction (HFpEF) in the TOPCAT trial, which enrolled patients with LVEF of 45% or greater. We utilized data from TOPCAT to assess the relationship between LVEF as well as outcomes and efficacy of spironolactone.

Methods And Results: We assessed differences in baseline characteristics and outcomes across LVEF categories in 3444 patients with HFpEF, and determined whether LVEF modified the treatment effect of spironolactone.

Regional variation in patients and outcomes in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial.

Background: Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) patients with heart failure and preserved left ventricular ejection fraction assigned to spironolactone did not achieve a significant reduction in the primary composite outcome (time to cardiovascular death, aborted cardiac arrest, or hospitalization for management of heart failure) compared with patients receiving placebo. In a post hoc analysis, an ≈4-fold difference was identified in this composite event rate between the 1678 patients randomized from Russia and Georgia compared with the 1767 enrolled from the United States, Canada, Brazil, and Argentina (the Americas).

Methods And Results: To better understand this regional difference in clinical outcomes, demographic characteristics of these populations and their responses to spironolactone were explored.

Cardiac structure and function and prognosis in heart failure with preserved ejection fraction: findings from the echocardiographic study of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) Trial.

Background: Abnormalities in cardiac structure and function in heart failure with preserved ejection fraction may help identify patients at particularly high risk for cardiovascular morbidity and mortality.

Methods And Results: Cardiac structure and function were assessed by echocardiography in a blinded core laboratory at baseline in 935 patients with heart failure with preserved ejection fraction (left ventricular ejection fraction ≥45%) enrolled in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial and related to the primary composite outcome of cardiovascular death, heart failure hospitalization, or aborted cardiac arrest, and its components. At a median follow-up of 2.

Cardiac structure and function in heart failure with preserved ejection fraction: baseline findings from the echocardiographic study of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial.

Background: Heart failure with preserved ejection fraction (HFpEF) is associated with substantial morbidity and mortality. Existing data on cardiac structure and function in HFpEF suggest significant heterogeneity in this population.

Methods And Results: Echocardiograms were obtained from 935 patients with HFpEF (left ventricular ejection fraction ≥45%) enrolled in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial before initiation of randomized therapy.

IMPROVE trial: a randomized controlled trial of patient-controlled analgesia for sickle cell painful episodes: rationale, design challenges, initial experience, and recommendations for future studies.

Background: The hallmark of sickle cell disease (SCD) is pain from a vaso-occlusive crisis. Although ambulatory pain accounts for most days in pain, pain is also the most common cause of hospitalization and is typically treated with parenteral opioids. The evidence base is lacking for most analgesic practice in SCD, particularly for the optimal opioid dosing for patient-controlled analgesia (PCA), in part because of the challenges of the trial design and conduct for this rare disease.

Dental composite restorations and neuropsychological development in children: treatment level analysis from a randomized clinical trial.

Background: Resin-based dental restorations may intra-orally release their components and bisphenol A. Gestational bisphenol A exposure has been associated with poorer executive functioning in children.

Objectives: To examine whether exposure to resin-based composite restorations is associated with neuropsychological development in children.

Dental composite restorations and psychosocial function in children.

Background And Objective: Resin-based dental materials may intraorally release their chemical components and bisphenol A. The New England Children's Amalgam Trial found that children randomized to amalgam had better psychosocial outcomes than those assigned to composites for posterior tooth restorations. The objective of this study was to examine whether greater exposure to dental composites is associated with psychosocial problems in children.

Rationale and design of the treatment of preserved cardiac function heart failure with an aldosterone antagonist trial: a randomized, controlled study of spironolactone in patients with symptomatic heart failure and preserved ejection fraction.

Background: Despite increasing prevalence of heart failure (HF) in patients with preserved ejection fraction (PEF), there are no available therapies proven to reduce morbidity and mortality. Aldosterone, a potent stimulator of myocardial and vascular fibrosis, may be a key mediator of HF progression in this population and is therefore an important therapeutic target.

Objective: The TOPCAT trial is designed to evaluate the effect of spironolactone, an aldosterone antagonist, on morbidity, mortality, and quality of life in patients with HF-PEF.

Opioid patient controlled analgesia use during the initial experience with the IMPROVE PCA trial: a phase III analgesic trial for hospitalized sickle cell patients with painful episodes.

Opioid analgesics administered by patient-controlled analgesia (PCA)are frequently used for pain relief in children and adults with sickle cell disease (SCD) hospitalized for persistent vaso-occlusive pain, but optimum opioid dosing is not known. To better define PCA dosing recommendations,a multi-center phase III clinical trial was conducted comparing two alternative opioid PCA dosing strategies (HDLI—higher demand dose with low constant infusion or LDHI—lower demand dose and higher constant infusion) in 38 subjects who completed randomization prior to trial closure. Total opioid utilization (morphine equivalents,mg/kg) in 22 adults was 11.

Methodological considerations with the use of urine samples for assessment of mercury excretion and markers of renal damage.

Objective: To provide recommendations for design and analysis of studies using urine specimens to evaluate renal function or mercury excretion in children.

Methods: An analysis of mercury, albumin, γ-glutamyl transpeptidase (γ-GT) and N-acetyl-β-D-glucosaminidase (NAG) concentrations was carried out.

Results: Mercury concentration and creatinine-corrected renal markers were higher in daytime compared with overnight samples.

The influence of urinary flow rate on mercury excretion in children.

Project: There is limited literature concerning the effect of urinary flow rate on mercury excretion at low-level exposure. The aim of the present study is to examine the influence of urinary flow rate on mercury excretion in children. Also of interest is the influence of flow rate on creatinine excretion and creatinine-corrected mercury, which arisearises with spot urine samples.

Neuropsychological function in school-age children with low mercury exposures.

The EPA reference dose for methylmercury (MeHg) was established using data from populations with greater exposures than those typical of the US. Few data are available on potential adverse health effects at lower levels. We examined relationships between hair mercury (Hg) levels and neuropsychological outcomes in a population of US children.

The normal menopause transition.

This paper presents analyses from perhaps the largest and most comprehensive prospective cohort study of mid-aged women--the Massachusetts Women's Health Study (MWHS)--with numbers sufficient to provide, for the first time, stable estimates of parameters in the normal menopause transition. The three questions addressed in this analysis are (i) what are the natural menopause transitions and when do they occur, (ii) what factors affect these transitions and (iii) what signs and/or symptoms accompany these transitions? The data were obtained primarily from 5 years of follow-up of 2570 women in Massachusetts who were aged 45-55 years as of January 1, 1982. An initial baseline cross-sectional survey (T0) yielded a total of 8050 completed responses with an overall response rate of 77%.

Immune function effects of dental amalgam in children: a randomized clinical trial.

Background: Dental amalgam is a widely used restorative material containing 50 percent elemental mercury that emits mercury vapor. No randomized clinical trials have determined whether there are adverse immunological effects associated with this low-level mercury exposure in children. The objective of this study was to evaluate a subpopulation of the participants in the New England Children's Amalgam Trial for in vitro manifestations of immunotoxic effects of dental amalgam.

Renal effects of dental amalgam in children: the New England children's amalgam trial.

Background: Mercury is nephrotoxic and dental amalgam is a source of mercury exposure.

Methods: Children 6-10 years of age (n = 534) with two or more posterior teeth with caries but no prior amalgam restorations, were randomized to one of two treatments--amalgam or resin composite (white fillings)--used for caries treatment during 5 years of follow-up. The primary outcome was change in IQ, but important secondary outcomes were effects on markers of glomerular and tubular kidney function: urinary excretion of albumin, alpha-1-microglobulin (A1M), gamma-glutamyl transpeptidase (gamma-GT), and N-acetyl-beta-d-glucosaminidase (NAG).

Design of the Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease (FREEDOM) Trial.

Background: Prior randomized trials suggested that revascularization of diabetic patients by coronary artery bypass grafting (CABG) produced results superior to balloon angioplasty. The introduction of drug-eluting stents (DESs) calls into question the relevance of past studies to the current era. The FREEDOM Trial is designed to determine whether CABG or percutaneous coronary intervention (PCI) is the superior approach for revascularization of diabetic patients.

Scalp hair and urine mercury content of children in the Northeast United States: the New England Children's Amalgam Trial.

Unlabelled: Children may be at particular risk from toxic effects of mercury (Hg). Previous studies of hair (organic) and urine (inorganic) Hg levels in US children were unable to assess Hg levels while accounting for exposure to amalgam dental restorations. This analysis describes, over a 5-year period, levels and correlates/predictors of scalp hair (H-Hg) and urinary (U-Hg) mercury in 534 New England Children's Amalgam Trial (NECAT) participants, aged 6-10 years and without exposure to dental amalgam at baseline.

Neuropsychological function in children with blood lead levels <10 microg/dL.

Clear adverse effects of blood lead levels >or=10 microg/dL have been documented in children. Given that the majority of US children have levels below 10 microg/dL, clarification of adverse effects below this cutoff value is needed. Our study evaluated the associations between blood lead levels <10 microg/dL and a broad spectrum of children's cognitive abilities.