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. METHODS: In 1,767 patients randomized to spironolactone or placebo in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial)-Americas study, we examined the incidence of WRF (doubling of serum creatinine) by treatment assignment. Associations between incident WRF and subsequent risk for the primary study endpoint of cardiovascular (CV) death, HFH, or aborted cardiac arrest and key secondary outcomes, including CV death, HFH, and all-cause mortality according to treatment assignment, were examined in time-updated Cox proportional hazards models with an interaction term. RESULTS: WRF developed in 260 (14.7%) patients with higher rates in those assigned to spironolactone compared to placebo (17.8% vs. 11.6%; odds ratio: 1.66; 95% confidence interval: 1.27 to 2.17; p < 0.001). Regardless of treatment, incident WRF was associated with increased risk for the primary endpoint (hazard ratio: 2.04; 95% confidence interval: 1.52 to 2.72; p < 0.001) after multivariable adjustment. Although there was no statistical interaction between treatment assignment and WRF regarding the primary endpoint (interaction p = 0.11), spironolactone-associated WRF was associated with lower risk of CV death (interaction p = 0.003) and all-cause mortality (interaction p = 0.001) compared with placebo-associated WRF. CONCLUSIONS: Among HFpEF patients enrolled in TOPCAT-Americas, spironolactone increased risk of WRF compared with placebo. Rates of CV death were lower with spironolactone in both patients with and without WRF.

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. Due to marked regional differences in characteristics and outcomes of the TOPCAT patients, with much lower events in patients enrolled in Russia/Georgia, we restricted our analyses on findings from patients enrolled from the Americas. Compared to patients without DM, patients with ITDM had approximately 2-fold increased risk for the primary end point, heart failure hospitalization, and myocardial infarction (hazard ratios: 1.80, 1.97, and 2.27, respectively) and approximately 50% increases in all-cause and CV mortality. The risks for these outcomes were also increased in patients with ITDM in comparison to patients with NITDM as well (hazard ratios: 1.63, 1.65, and 2.73, respectively, and approximately 40% increases in all-cause and CV mortality). Patients with NITDM had similar risks for the primary end point and all secondary end points as patients without DM. In conclusion, the apparent increased risk of adverse outcomes in patients with heart failure and preserved left ventricular ejection fraction and ITDM merits future research to improve the prognosis of these high-risk patients.

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+] <3.5 mmol/l) and hyperkalemia (K+ ≥5.5 mmol/l) among both placebo- and spironolactone-assigned patients in TOPCAT. Factors associated with incident hypokalemia and hyperkalemia and the relationship between incident K+ abnormalities and the risk of subsequent mortality were analyzed in multivariable regression models restricted to the Americas. RESULTS: In the Americas, assignment to spironolactone increased risk for hyperkalemia (hazard ratio 3.21, 95% confidence interval 2.46-4.20, P < .001) and reduced risk of hypokalemia (hazard ratio 0.43, 95% confidence interval 0.34-0.55, P < .001). Assignment to spironolactone, lower estimated glomerular filtration rate, higher baseline K+, diabetes, and lower hemoglobin were associated with incident hyperkalemia, whereas assignment to placebo, lower K+, younger age, lower estimated glomerular filtration rate, and use of diuretics at baseline were associated with hypokalemia. The combination of spironolactone and an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker was associated with incremental risk for hyperkalemia and protection from hypokalemia. Independent of region, both hypokalemia and hyperkalemia, were associated with higher risk for cardiovascular and all-cause mortality in multivariable-adjusted Cox regression models. CONCLUSIONS: Both hyperkalemia and hypokalemia are associated with heightened risk for mortality in HF-PEF. Use of spironolactone in this population requires careful laboratory surveillance of K+ and creatinine, particularly in high-risk groups.

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. The detection of a greater than expected incidence of deterioration in renal function, occurring in 6.1% of patients in the spironolactone arm compared with 3.9% in the placebo arm (P = 0.009), led to an in-depth DSMB review of associated study medication withdrawals and adverse events. The trial continued uninterrupted throughout the review, which reached the conclusions that spironolactone-associated renal dysfunction did not compromise overall patient safety or interfere with a perceived efficacy signal. Although no discrete mechanism for the spironolactone-associated renal adverse event signal was identified, likely possibilities are discussed. In clinical trials, DSMBs and co-ordinating centres should have the resources to detect, investigate, and adjudicate unexpected safety issues, with goals of ensuring patient safety and preserving the potential for detection of therapeutic effectiveness. In TOPCAT, spironolactone-associated renal dysfunction emerged as a potentially trial-threatening adverse event and, although clinically important, did not lead to compromise of patient safety, trial interruption, termination, or apparent loss of treatment effectiveness.

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. METHODS: QRS duration was analyzed as a dichotomous variable (≥120 ms or <120 ms) and as a continuous variable to determine its relation to the primary outcome (composite of cardiovascular death, aborted cardiac arrest, or HF hospitalization [HFH]) and to each component of the primary outcome. Multivariate analyses were conducted in the entire study cohort as well as in separate analyses for subjects enrolled only from North and South America, or from Russia and Georgia. RESULTS: The QRS duration of ≥120 ms was independently associated with an increased risk of the primary outcome (p = 0.009) and HFH (p = 0.003) in the entire study cohort and in the subset enrolled in the Americas. There was a linear relation of QRS duration with risk of the primary outcome and HFH. No interaction was observed between treatment with spironolactone and QRS duration. The risk of adverse outcomes was increased independently of the type of conduction abnormality underlying prolonged QRS duration. CONCLUSIONS: This post hoc analysis demonstrated that prolonged QRS duration identifies HFPEF subjects at a higher risk of adverse clinical outcomes and that spironolactone had a similar effect on outcomes independent of QRS duration. (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function [TOPCAT]; NCT00094302).

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. Ejection fraction ranged from 44 to 85%. Patients with higher ejection fraction were older, more likely to be female, less likely to have a history of myocardial infarction, and more likely to have a history of hypertension and diabetes. The incidence of the primary endpoint and cardiovascular death was highest in patients at the lower end of the ejection fraction spectrum. Ejection fraction modified the spironolactone treatment effect, particularly in the patients enrolled in the Americas, for the primary outcome (P = 0.046) and for heart failure hospitalization (P = 0.039), with stronger estimated benefits of spironolactone at the lower end of the ejection fraction spectrum with respect to the primary endpoint (LVEF <50%: HR 0.72, 95% CI 0.50, 1.05; LVEF ≥60%: HR 0.97, 95% CI 0.76, 1.23) and heart failure hospitalization (LVEF <50%: HR 0.76, 95% CI 0.46, 1.27; LVEF ≥60%: HR 0.98, 95% CI 0.74, 1.30). CONCLUSION: In patients with HFpEF enrolled in TOPCAT, patient characteristics and outcomes varied substantially by LVEF. The potential efficacy of spironolactone was greatest at the lower end of the LVEF spectrum. CLINICALTRIALSGOV NUMBER: NCT00094302.

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. Patients from Russia/Georgia were younger, had less atrial fibrillation and diabetes mellitus, but were more likely to have had prior myocardial infarction or a hospitalization for heart failure. Russia/Georgia patients also had lower left ventricular ejection fraction and creatinine but higher diastolic blood pressure (all P<0.001). Hyperkalemia and doubling of creatinine were more likely and hypokalemia was less likely in patients receiving spironolactone in the Americas with no significant treatment effects in Russia/Georgia. All clinical event rates were markedly lower in Russia/Georgia, and there was no detectable impact of spironolactone on any outcomes. In contrast, in the Americas, the rates of the primary outcome, cardiovascular death, and hospitalization for heart failure were significantly reduced by spironolactone. CONCLUSIONS: This post hoc analysis demonstrated greater potassium and creatinine changes and possible clinical benefits with spironolactone in patients with heart failure and preserved ejection fraction from the Americas. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302.

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 2.9 years, 244 patients experienced the primary outcome. Left ventricular hypertrophy (adjusted hazard ratio, 1.52; 95% confidence interval, 1.16-2.00), elevated left ventricular filling pressure (E/E'; adjusted hazard ratio 1.05 per 1 integer increase; 95% confidence interval, 1.02-1.07), and higher pulmonary artery pressure assessed by the tricuspid regurgitation velocity (hazard ratio, 1.23 per 0.5 m/s increase; 95% confidence interval, 1.02-1.49) were associated with the composite outcome and heart failure hospitalization alone after adjusting for clinical and laboratory variables. The risk of adverse outcome associated with left ventricular hypertrophy was additive to the risk associated with elevated E/E'. CONCLUSIONS: Among heart failure with preserved ejection fraction patients enrolled in TOPCAT, left ventricular hypertrophy, higher left ventricular filling pressure, and higher pulmonary artery pressure were predictive of heart failure hospitalization, cardiovascular death, or aborted cardiac arrest independent of clinical and laboratory predictors. These features, both alone and in combination, identify heart failure with preserved ejection fraction patients at particularly high risk for cardiovascular morbidity and mortality. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302.

Spironolactone for heart failure with preserved ejection fraction.

BACKGROUND: Mineralocorticoid-receptor antagonists improve the prognosis for patients with heart failure and a reduced left ventricular ejection fraction. We evaluated the effects of spironolactone in patients with heart failure and a preserved left ventricular ejection fraction. METHODS: In this randomized, double-blind trial, we assigned 3445 patients with symptomatic heart failure and a left ventricular ejection fraction of 45% or more to receive either spironolactone (15 to 45 mg daily) or placebo. The primary outcome was a composite of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure. RESULTS: With a mean follow-up of 3.3 years, the primary outcome occurred in 320 of 1722 patients in the spironolactone group (18.6%) and 351 of 1723 patients in the placebo group (20.4%) (hazard ratio, 0.89; 95% confidence interval [CI], 0.77 to 1.04; P=0.14). Of the components of the primary outcome, only hospitalization for heart failure had a significantly lower incidence in the spironolactone group than in the placebo group (206 patients [12.0%] vs. 245 patients [14.2%]; hazard ratio, 0.83; 95% CI, 0.69 to 0.99, P=0.04). Neither total deaths nor hospitalizations for any reason were significantly reduced by spironolactone. Treatment with spironolactone was associated with increased serum creatinine levels and a doubling of the rate of hyperkalemia (18.7%, vs. 9.1% in the placebo group) but reduced hypokalemia. With frequent monitoring, there were no significant differences in the incidence of serious adverse events, a serum creatinine level of 3.0 mg per deciliter (265 µmol per liter) or higher, or dialysis. CONCLUSIONS: In patients with heart failure and a preserved ejection fraction, treatment with spironolactone did not significantly reduce the incidence of the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure. (Funded by the National Heart, Lung, and Blood Institute; TOPCAT ClinicalTrials.gov number, NCT00094302.).

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. Average age was 70±10 years, 49% were women, 14% were of African descent, and comorbidities were highly prevalent. Centralized quantitative analysis in a blinded core laboratory demonstrated a mean left ventricular ejection fraction of 59.3±7.9%, with prevalent concentric left ventricular remodeling (34%) and hypertrophy (43%), and left atrial enlargement (53%). Diastolic dysfunction was present in 66% of gradable participants and was significantly associated with greater left ventricular hypertrophy and a higher prevalence of left atrial enlargement. Doppler evidence of pulmonary hypertension was present in 36%. At least 1 measure of structural heart disease was present in 93% of patients. CONCLUSIONS: Patients enrolled in TOPCAT demonstrated heterogeneous patterns of ventricular remodeling, with high prevalence of structural heart disease, including left ventricular hypertrophy and left atrial enlargement, in addition to pulmonary hypertension, each of which has been associated with adverse outcomes in HFpEF. Diastolic function was normal in approximately one third of gradable participants, highlighting the heterogeneity of the cardiac phenotype in this syndrome. These findings deepen our understanding of the TOPCAT trial population and expand our knowledge of the diversity of the cardiac phenotype in HFpEF. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302.

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. PURPOSE: The purpose of this report is to describe our Network's experiences with protocol development, implementation, and analysis, including overall study design, the value of pain assessments rather than 'crisis' resolution as trial endpoints, and alternative statistical analysis strategies. METHODS: The Improving Pain Management and Outcomes with Various Strategies (IMPROVE) PCA trial was a multisite inpatient randomized controlled trial comparing two PCA-dosing strategies in adults and children with SCD and acute pain conducted by the SCD Clinical Research Network. The specified primary endpoint was a 25-mm change in a daily average pain intensity using a Visual Analogue Scale, and a number of related pain intensity and pain interference measures were selected as secondary efficacy outcomes. A time-to-event analysis strategy was planned for the primary endpoint. RESULTS: Of 1116 individuals admitted for pain at 31 participating sites over a 6-month period, 38 were randomized and 4 withdrawn. The trial was closed early due to poor accrual, reflecting a substantial number of challenges encountered during trial implementation. LIMITATIONS: While some of the design issues were unique to SCD or analgesic studies, many of the trial implementation challenges reflected the increasing complexity of conducting clinical trials in the inpatient setting with multiple care providers and evolving electronic medical record systems, particularly in the context of large urban academic medical centers. LESSONS LEARNED: Complicated clinical organization of many sites likely slowed study initiation. More extensive involvement of research staff and site principal investigator in the clinical care operations improved site performance. During the subsequent data analysis, alternative statistical approaches were considered, the results of which should inform future efficacy assessments and increase future trial recruitment success by allowing substantial reductions in target sample size. CONCLUSIONS: A complex randomized analgesic trial was initiated within a multisite disease network seeking to provide an evidence base for clinical care. A number of design considerations were shown to be feasible in this setting, and several pain intensity and pain interference measures were shown to be sensitive to time- and treatment-related improvements. While the premature closure and small sample size precluded definitive conclusions regarding treatment efficacy, this trial furnishes a template for design and implementation considerations that should improve future SCD analgesic trials.

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. METHODS: Secondary analysis of treatment level data from the New England Children's Amalgam Trial, a 2-group randomized safety trial conducted from 1997 to 2006. Children (N=534) aged 6-10 y with ≥2 posterior tooth caries were randomized to treatment with amalgam or resin-based composites (bisphenol-A-diglycidyl-dimethacrylate-composite for permanent teeth; urethane dimethacrylate-based polyacid-modified compomer for primary teeth). Neuropsychological function at 4- and 5-year follow-up (N=444) was measured by a battery of tests of executive function, intelligence, memory, visual-spatial skills, verbal fluency, and problem-solving. Multivariable generalized linear regression models were used to examine the association between composite exposure levels and changes in neuropsychological test scores from baseline to follow-up. For comparison, data on children randomized to amalgam treatment were similarly analyzed. RESULTS: With greater exposure to either dental composite material, results were generally consistent in the direction of slightly poorer changes in tests of intelligence, achievement or memory, but there were no statistically significant associations. For the four primary measures of executive function, scores were slightly worse with greater total composite exposure, but statistically significant only for the test of Letter Fluency (10-surface-years ß=-0.8, SE=0.4, P=0.035), and the subtest of color naming (ß=-1.5, SE=0.5, P=0.004) in the Stroop Color-Word Interference Test. Multivariate analysis of variance confirmed that the negative associations between composite level and executive function were not statistically significant (MANOVA, P=0.18). Results for greater amalgam exposure were mostly nonsignificant in the opposite direction of slightly improved scores over follow-up. CONCLUSIONS: Dental composite restorations had statistically insignificant associations of small magnitude with impairments in neuropsychological test change scores over 4- or 5-years of follow-up in this trial.

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. METHODS: Analysis of treatment-level data from the New England Children's Amalgam Trial, a 2-group randomized safety trial comparing amalgam with the treatment plan of bisphenol A-glycidyl methacrylate (bisGMA)-based composite and urethane dimethacrylate-based polyacid-modified composite (compomer), among 534 children aged 6 to 10 years at baseline. Psychosocial function at follow-up (n = 434) was measured by using the self-reported Behavior Assessment System for Children (BASC-SR) and parent-reported Child Behavior Checklist (CBCL). RESULTS: Children with higher cumulative exposure to bisGMA-based composite had poorer follow-up scores on 3 of 4 BASC-SR global scales: Emotional Symptoms (ß = 0.8, SE = 0.3, P = .003), Clinical Maladjustment (ß = 0.7, SE = 0.3, P = .02), and Personal Adjustment (ß = -0.8, SE = 0.2, P = .002). Associations were stronger with posterior-occlusal (chewing) surfaces, where degradation of composite was more likely. For CBCL change, associations were not statistically significant. At-risk or clinically significant scores were more common among children with greater exposure for CBCL Total Problem Behaviors (16.3% vs 11.2%, P-trend = .01) and numerous BASC-SR syndromes (eg, ≥ 13 vs 0 surface-years, Interpersonal Relations 13.7% vs 4.8%, P-trend = .01). No associations were found with compomer, nor with amalgam exposure levels among children randomized to amalgam. CONCLUSIONS: Greater exposure to bisGMA-based dental composite restorations was associated with impaired psychosocial function in children, whereas no adverse psychosocial outcomes were observed with greater urethane dimethacrylate-based compomer or amalgam treatment levels.

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. METHODS: Up to 3,515 patients with HF-PEF will be randomized in double-blind fashion to treatment with spironolactone (target dose 30 mg daily) or matching placebo. Eligible patients include those with age ≥50 years, left ventricular ejection fraction ≥45%, symptomatic HF, and either a hospitalization for HF within the prior year or an elevated natriuretic peptide level (B-type natriuretic peptide ≥100 pg/mL or N-terminal pro-B-type natriuretic peptide ≥360 pg/mL) within the 60 days before randomization. Patients with uncontrolled hypertension and those with known infiltrative or hypertrophic cardiomyopathy are excluded. The primary end point is the composite of cardiovascular death, hospitalization for HF, or aborted cardiac arrest. Key secondary end points include quality of life, nonfatal cardiovascular events, and new-onset atrial fibrillation. Ancillary studies of echocardiography, tonometry, and cardiac biomarkers will provide more insight regarding this understudied population and the effects of spironolactone therapy. CONCLUSION: TOPCAT is designed to assess definitively the role of spironolactone in the management of 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 (HDLI­higher demand dose with low constant infusion or LDHI­lower 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 11.6 ± 2.6 and 4.7 ± 0.9 in the HDLI andin the LDHI arms, respectively, and in 12 children it was 3.7 ± 1.0 and 5.8 ± 2.2, respectively. Opioid-related symptoms were mild and similar in both PCA arms (mean daily opioid symptom intensity score: HDLI0.9 ± 0.1, LDHI 0.9 ± 0.2). The slow enrollment and early study termination limited conclusions regarding superiority of either treatment regimen. This study adds to our understanding of opioid PCA usage in SCD. Future clinical trial protocol designs for opioid PCA may need to consider potential differences between adults and children in PCA usage.

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-ß-D-glucosaminidase (NAG) concentrations was carried out. RESULTS: Mercury concentration and creatinine-corrected renal markers were higher in daytime compared with overnight samples. Excretion rates increased with urinary flow rate. γ-GT and NAG concentrations decreased with storage time at -20°C. Differences by age, sex and race were noted. CONCLUSIONS: We recommend use of these creatinine-corrected markers and collection of timed overnight urine samples, stored at -70°C, with control for urinary flow rate, age, sex and race in statistical models.

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. PROCEDURE: A substudy of the New England Children's Amalgam Trial collected pairs of urine samples from children aged 10-16 years: a timed overnight collection and a spot daytime sample collected the following day. These samples were analyzed for mercury and creatinine concentration. Regression analysis was used to model the effect of urinary flow rate in the timed overnight samples. A paired t-test compared concentrations and creatinine-corrected mercury between overnight and daytime samples. RESULTS: Creatinine excretion rate (mg/h) increased significantly with urinary flow rate (mL/h), whereas creatinine concentration (g/L) decreased with flow rate. We found a non-significant increase in mercury excretion rate (ng/h) with flow rate, and mercury concentration decreased with flow rate. Mercury and creatinine concentrations were significantly higher in the overnight compared to daytime samples. For creatinine-corrected mercury, no significant impact of urinary flow rate was found. CONCLUSIONS: Although the creatinine excretion rate, and probably the mercury excretion rate, increased with urinary flow rate, the mercury/creatinine ratio seemed relatively unaffected by urinary flow rate.

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. This study included data from 355 children ages 6-10 enrolled in the New England Children's Amalgam Trial. Data on total hair Hg levels, sociodemographic information and neuropsychological function were collected. We evaluated associations between hair Hg and neuropsychological test scores with linear regression methods and used generalized additive models to determine the shape of associations that departed from linearity. Models controlled for relevant covariates, including the potential beneficial effects of consuming fish. In adjusted models, we observed no significant linear relationships between hair Hg level and any test score. Significant departures from linearity were identified for WIAT Math Reasoning and WRAMVA Visual-Motor Composite scores. The association was positive for hair Hg levels below 0.5 microg/g and negative for levels between 0.5 and 1.0 microg/g. Overall, test scores of children with hair Hg levels 1.0 microg/g appeared to be lower than those of children with levels < 1.0 microg/g, but few children had levels in this upper range and these differences did not reach statistical significance. Hair Hg levels below 1.0 microg/g in US school-age children were not adversely related to neuropsychological function.

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. METHODS: The authors conducted a randomized clinical trial in which children requiring dental restorative treatment were randomly assigned to receive either amalgam for posterior restorations or resin-based composite restorations. They assessed 66 children, aged 6 to 10 years, for total white blood cell counts, specific lymphocyte (T-cell and B-cell) counts and lymphocyte, neutrophil and monocyte responsiveness across a five-year period. Because of the small number of participants, the authors acknowledge that the study is exploratory in nature and has limited statistical power. RESULTS: The mean number of tooth surfaces restored during the five-year period was 7.8 for the amalgam group and 10.1 for the composite group. In the amalgam group, there was a slight, but not statistically significant, decline in responsiveness of T cells and monocytes at five to seven days after treatment; the authors consistently observed no differences at six, 12 or 60 months. CONCLUSIONS: The findings of this study confirm that treatment of children with amalgam restorations leads to increased, albeit low-level, exposure to mercury. In this exploratory analysis of immune function, amalgam exposure did not cause overt immune deficits, although small transient effects were observed five to seven days after restoration placement. CLINICAL IMPLICATIONS: These findings suggest that immunotoxic effects of amalgam restorations are minimal and transient in children and most likely do not need to be of concern to practitioners considering the use of this restorative dental material.