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Andrea V Margulis,1 Manel Pladevall,1 Nuria Riera-Guardia,1 Cristina Varas-Lorenzo,1 Lorna Hazell,2,3 Nancy D Berkman,4 Meera Viswanathan,4 Susana Perez-Gutthann,1 1RTI Health Solutions, Barcelona, Spain; 2Drug Safety Research Unit, Southampton, UK; 3Associate Department of the School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK; 4RTI International, Research Triangle Park, NC, USA Background: The study objective was to compare the Newcastle–Ottawa Scale (NOS) and the RTI item bank (RTI-IB) and estimate interrater agreement using the RTI-IB within a systematic review on the cardiovascular safety of glucose-lowering drugs. Methods: We tailored both tools and added four questions to the RTI-IB. Two reviewers assessed the quality of the 44 included studies with both tools, (independently for the RTI-IB) and agreed on which responses conveyed low, unclear, or high risk of bias. For each question in the RTI-IB (n=31), the observed interrater agreement was calculated as the percentage of studies given the same bias assessment by both reviewers; chance-adjusted interrater agreement was estimated with the first-order agreement coefficient (AC1) statistic. Results: The NOS required less tailoring and was easier to use than the RTI-IB, but the RTI-IB produced a more thorough assessment. The RTI-IB includes most of the domains measured in the NOS. Median observed interrater agreement for the RTI-IB was 75% (25th percentile [p25] =61%; p75 =89%); median AC1 statistic was 0.64 (p25 =0.51; p75 =0.86). Conclusion: The RTI-IB facilitates a more complete quality assessment than the NOS but is more burdensome. The observed agreement and AC1 statistic in this study were higher than those reported by the RTI-IB's developers. Keywords: systematic review, meta-analysis, quality assessment, AC1

Rationale: Adherence to inhaled corticosteroid (ICS) medication is known to be low overall, but tends to be lower among African-American patients when compared with white patients.Objectives: To understand the factors that contribute to ICS adherence among African-American and white adults with asthma.Methods: Eligible individuals had a prior diagnosis of asthma, one or more ICS prescriptions, and were members of a large health maintenance organization in southeast Michigan. Individuals were sent a survey that included questions about internal factors (e.g., patient beliefs, knowledge, and motivation) and external factors (e.g., socioeconomic status, barriers to care, social support, and stressors) potentially related to ICS adherence. Adherence was calculated using electronic prescription and fill data. Stepwise regression was used to identify factors associated with adherence before and after stratifying by race-ethnicity.Measurements and Main Results: Surveys were returned by 1,006 (56.3%) of 1,787 eligible patients. Adjusting for internal factors, but not external factors, diminished the relationship between race-ethnicity and ICS adherence. Among African-American patients, readiness to take ICS medication was the only internal or external factor significantly associated with ICS adherence; it explained 5.6% of the variance in adherence. Among white patients, perceived ICS necessity, ICS knowledge, doctors being perceived as the source of asthma control, and readiness to take medication were the internal factors associated with ICS adherence; these accounted for 19.8% of the variance in adherence.Conclusions: Factors associated with ICS adherence appear to differ between African-American and white patients, suggesting that group-specific approaches are needed to improve adherence. [ABSTRACT FROM AUTHOR]

Objective: Confirmatory factor analysis (CFA) was used to test the hypothesis that the components of the metabolic syndrome are manifestations of a single common factor.Research Design and Methods: Three different datasets were used to test and validate the model. The Spanish and Mauritian studies included 207 men and 203 women and 1,411 men and 1,650 women, respectively. A third analytical dataset including 847 men was obtained from a previously published CFA of a U.S. population. The one-factor model included the metabolic syndrome core components (central obesity, insulin resistance, blood pressure, and lipid measurements). We also tested an expanded one-factor model that included uric acid and leptin levels. Finally, we used CFA to compare the goodness of fit of one-factor models with the fit of two previously published four-factor models.Results: The simplest one-factor model showed the best goodness-of-fit indexes (comparative fit index 1, root mean-square error of approximation 0.00). Comparisons of one-factor with four-factor models in the three datasets favored the one-factor model structure. The selection of variables to represent the different metabolic syndrome components and model specification explained why previous exploratory and confirmatory factor analysis, respectively, failed to identify a single factor for the metabolic syndrome.Conclusions: These analyses support the current clinical definition of the metabolic syndrome, as well as the existence of a single factor that links all of the core components. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to assess the quality of outpatient care received by patients with congestive heart failure (CHF) and whether differences in care and outcomes exist by race/ethnicity.Background: Appropriate outpatient CHF management can improve patient well-being and reduce the need for costly inpatient care. Yet, little is known regarding outpatient CHF management or whether differences in this care exist by race/ethnicity.Methods: Using automated data sources, we identified a cohort of insured patients seen in an outpatient setting for CHF between September 1992 and August 1993. Medical record abstraction was used to confirm diagnosis of CHF. Patients (N = 566) were followed until September 1998. Race/ethnicity differences in outpatient management and medical care utilization were assessed using generalized estimating equations. Differences in mortality and hospitalization for CHF, controlling for patient characteristics and outpatient management, were assessed using Cox and Andersen-Gill models, respectively.Results: With the exception of beta blocker use and primary care visit frequency, few differences by race/ethnicity in patient characteristics and CHF management were found. However, older black patients had more hospital use both at baseline and during follow up. These differences persisted after adjusting for patient characteristics and clinical management. No race/ethnicity differences were found in mortality.Conclusions: In an insured population, older black patients with CHF have substantially more hospital use than older white patients. This increased use was not explained by differences in CHF outpatient management. Further research is needed to understand why race/ethnicity differences in hospital use are observed among older patients with CHF. [ABSTRACT FROM AUTHOR]

An abstract of the article "Race-Ethnic Differences in Factors Associated with Inhaled Steroid Adherence Among Adults with Asthma" by E. Peterson and colleagues is presented.

Purpose: Acute liver injury (ALI) is an important adverse drug reaction. We estimated the positive predictive values (PPVs) of ICD-10-GM codes of ALI used in an international postauthorisation safety study (PASS)., Methods: Analyses used routine data (2007 to 2016, adults) from a German academic hospital in a cross-sectional design. Two algorithms from the PASS were applied to extract potential cases from the hospital information system: specific end point (A) (discharge diagnosis of liver disease-specific codes) and less specific end point (B) (discharge and outpatient-specific and nonspecific codes suggestive of liver injury). ALI cases were confirmed on the basis of plasma liver enzyme activity elevation. Secondary analysis was performed following exclusion of cases with known cancer, chronic liver, biliary and pancreatic disease, heart failure, and alcohol-related disorders, as applied in the PASS., Results: On the basis of ICD codes: outcome A, 154 cases (143 with case notes and lab data for case verification); outcome B, 485 cases (357 with case notes and lab data). ALI was confirmed in 71 outcome A cases, PPV of 49.7% (95% confidence interval [CI], 41.2%-58.1%), and 100 outcome B cases, PPV of 28.0% (95% CI, 23.4%-33.0%). Applying exclusion criteria increased PPV (95% CI) to 62.7% (50.0%-74.2%) for outcome A and 45.7% (37.2%-54.3%) for outcome B., Conclusions: In safety studies on hepatotoxicity based on routine data using ICD-10-GM discharge codes and when validation of potential cases is not feasible, only the more specific codes should be used to describe ALI, and competing diagnoses for liver injury should be excluded to avoid substantial misclassification., (© 2019 John Wiley & Sons, Ltd.)

Background: The results of observational studies evaluating and comparing the cardiovascular safety of glitazones, metformin and sufonylureas are inconsistent.To conduct and evaluate heterogeneity in a meta-analysis of observational studies on the risk of acute myocardial infarction (AMI) or stroke in patients with type 2 diabetes using non-insulin blood glucose-lowering drugs (NIBGLD)., Methods: We systematically identified and reviewed studies evaluating NIBGLD in patients with type 2 diabetes indexed in Medline, Embase, or the Cochrane Library that met prespecified criteria. The quality of included studies was assessed with the RTI item bank. Results were combined using fixed- and random-effects models, and the Higgins I(2) statistic was used to evaluate heterogeneity. Sensitivity analyses by study quality were conducted., Results: The summary relative risk (sRR) (95% CI) of AMI for rosiglitazone versus pioglitazone was 1.13 (1.04-1.24) [I(2) = 55%]. In the sensitivity analysis, heterogeneity was reduced [I(2) = 16%]. The sRR (95% CI) of stroke for rosiglitazone versus pioglitazone was 1.18 (1.02-1.36) [I(2)  = 42%]. There was strong evidence of heterogeneity related to study quality in the comparisons of rosiglitazone versus metformin and rosiglitazone versus sulfonylureas (I (2) ≥ 70%). The sRR (95% CI) of AMI for sulfonylurea versus metformin was 1.24 (1.14-1.34) [I(2) = 41%] and for pioglitazone versus metformin was 1.02 (0.75-1.38) [I(2) = 17%]. Sensitivity analyses decreased heterogeneity in most comparisons., Conclusion/interpretation: Sulfonylureas increased the risk of AMI by 24% compared with metformin; an imprecise point estimate indicated no difference in risk of AMI when comparing pioglitazone with metformin. The presence of heterogeneity precluded any conclusions on the other comparisons. The quality assessment was valuable in identifying methodological problems in the individual studies and for analysing potential sources of heterogeneity.

Purpose: The purpose of this study was to assess whether providing medication adherence information with or without motivational interviewing improves diabetes and lipid control., Methods: Study participants were adult members of a health system in southeast Michigan, were using both oral diabetes and lipid-lowering medications, and had glycated hemoglobin (A1C) or low-density lipoprotein cholesterol (LDL-C) levels not at goal. Participants were randomly assigned to receive usual care (UC), n = 567; have medication adherence information (AI) provided to their physician, n = 569; or have AI and receive motivational interviewing (MI) though trained staff (AI + MI), n = 556. Primary outcomes were A1C and LDL-C levels at 18 months post randomization., Results: Primary outcomes were not significantly different between patients in the AI or AI + MI study arms when compared with UC. Similarly, neither oral diabetes nor lipid-lowering medication adherence was significantly different between groups. Patient participation in the AI + MI arm was low and limit the interpretation of the study results, but post hoc analysis of the AI + MI study arm showed that the number of MI sessions received was positively associated with only oral diabetes medication adherence., Conclusion: Neither AI nor MI significantly improved diabetes and lipid control when compared with UC. Moreover, patient participation appeared to be a particular barrier for MI., (© 2014 The Author(s).)

Background: Patients with type 2 diabetes mellitus (T2DM) are at high risk of heart failure. A summary of the effects of blood glucose-lowering drugs other than glitazones on the risk of heart failure in routine clinical practice is lacking. The objective of this study was to conduct a systematic review and meta-analysis of observational studies on the risk of heart failure when using blood glucose-lowering drugs., Methods: We systematically identified and reviewed cohort and case-control studies in which the main exposure of interest was noninsulin blood glucose-lowering medications in patients with T2DM. We searched Medline, Embase, and the Cochrane Library to identify publications meeting prespecified eligibility criteria. The quality of included studies was assessed with the Newcastle-Ottawa Scale and the RTI item bank. Results were combined using fixed and random-effects models when at least 3 independent data points were available for a drug-drug comparison., Results: The summary relative risk of heart failure in rosiglitazone users versus pioglitazone users (95% CI) was 1.16 (1.05-1.28) (5 cohort studies). Heterogeneity was present (I2 = 66%). For new users (n = 4) the summary relative risk was 1.21 (1.14-1.30) and the heterogeneity was reduced (I2 = 31%);. The summary relative risk for rosiglitazone versus metformin was 1.36 (95% CI, 1.17-1.59) (n = 3). The summary relative risk (95% CI) of heart failure in sulfonylureas users versus metformin users was 1.17 (95% CI, 1.06-1.29) (5 cohort studies; I2 = 24%) and 1.22 (1.02-1.46) when restricted to new users (2 studies).Information on other comparisons was very scarce. Information on dose and duration of treatment effects was lacking for most comparisons. Few studies accounted for disease severity; therefore, confounding by indication might be present in the majority of the within-study comparisons of this meta-analysis., Conclusions: Use of glitazones and sulfonylureas was associated with an increased risk of heart failure compared with metformin use. However, indication bias cannot be ruled out. Ongoing large multidatabase studies will help to evaluate the risk of heart failure in treated patients with diabetes, including those using newer blood glucose-lowering therapies.

Purpose: To find out whether the MTHFR rs1801133 polymorphism is a risk factor for male infertility in the Spanish population. To determine if a pattern of sperm DNA hypomethylation at the paternally imprinted loci H19-ICR and/or IG-DMR is related to the MTHFR rs1801133 polymorphism and/or CTCFL mutations., Methods: One hundred and seven samples from individuals who sought consultation for fertility problems and twenty-five semen samples from sperm donors were analyzed. The MTHFR rs1801133 SNP was analyzed in all samples by the PCR-RFLP method. We compared the distribution of the genotypes between control and infertile populations and among the groups of patients with altered seminal parameters. In those patients with the most severe hypomethylation pattern (n = 12) we also analyzed the CTCFL protein-coding exons by sequencing., Results: There were no significant differences in the distribution of the genotypes among the control and infertile populations. Moreover, none of the genotypes were associated, neither to the characteristics of the seminogram, nor to the presence of sperm DNA hypomethylation. We did not identify frameshift, nonsense or missense mutations of the CTCFL gene., Conclusions: The MTHFR rs1801133 polymorphism is not associated with male infertility in the Spanish population. Neither the MTHFR polymorphism, nor CTCFL mutations explain a pattern of sperm hypomethylation at paternally imprinting loci.

Despite ezetimibe's ability to reduce serum cholesterol levels, there are concerns over its vascular effects and whether it prevents or ameliorates atherosclerotic disease (AD). The aims of this study were to estimate the effect of ezetimibe use on major AD events and all-cause mortality and to compare these associations to those observed for hydroxymethylglutaryl coenzyme A reductase inhibitor (statin) use. A total of 367 new ezetimibe users were identified from November 1, 2002, to December 31, 2009. These subjects were aged ≥18 years and had no previous statin use. One to 4 statin user matches were identified for each ezetimibe user, resulting in a total of 1,238 closely matched statin users. Pharmacy data and drug dosage information were used to estimate a moving window of ezetimibe and statin exposure for each day of study follow-up. The primary outcome was a composite of major AD events (coronary heart disease, cerebrovascular disease, and peripheral vascular disease events) and all-cause death. Ezetimibe use (odds ratio 0.33, 95% confidence interval 0.13 to 0.86) and statin use (odds ratio 0.61, 95% confidence interval 0.36 to 1.04) were associated with reductions in the likelihood of the composite outcome. These protective associations were most significant for cerebrovascular disease events and all-cause death. Subgroup analyses by gender, race or ethnicity, history of AD, diabetes status, and estimated renal function showed consistent estimates across strata, with no significant differences between ezetimibe and statin use. In conclusion, ezetimibe appeared to have a protective effect on major AD events and all-cause death that was not significantly different from that observed for statin use., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The topic of imprinting defects present in the sperm of infertile patients has been addressed by several reports in the last few years. However, whether methylation abnormalities at one or few CpGs within an imprinted locus are pathological is a matter of debate. Moreover, whether imprinting anomalies in sperm could interfere with fertility treatment outcomes is still unknown. In this report we analyze the sperm DNA methylation profile of H19-ICR, KvDMR, SNRPN-ICR, IG-DMR and MEG3-DMR by pyrosequencing in 107 infertile men series and a control population of 30 proven fertile males. DNA methylation was statistically evaluated from two points of view: first, the methylation of each CpG was analyzed in the control population and the mean, standard deviation and range were determined and compared with infertile population data; second, in order to define altered methylation patterns for each region, a hierarchical cluster analysis was performed by which individuals were grouped in different clusters according to the degree of similarity of their methylation pattern. Two pieces of data supported the results obtained in the multi-variate analysis: the classification of the vast majority of control individuals in clusters with normal methylation patterns and the significant differences in methylation levels found between individuals within the normal and abnormal clusters. Individuals included in normal and abnormal methylation clusters were compared according to seminal parameters as well as to the outcome of assisted reproduction.

Objectives: To describe lipid management over time in a cohort of insured patients with diabetes and evaluate differences between African American and white patients., Study Design: Automated claims data were used to identify a cohort of 11,411 patients with diabetes in 1997 to 1998. Patients were followed through 2007., Methods: Rates of hypercholesterolemia testing, treatment, and goal attainment were measured annually. Treatment was determined by a claim for lipid-lowering agents, and goal attainment was defined as a low-density lipoprotein cholesterol (LDL-C) level <100 mg/dL., Results: During the study period, LDL-C testing increased from 48% to 70% among African American patients and from 61% to 77% among white patients. Treatment with lipid-lowering drugs increased from 23% to 56% among African American patients and 33% to 61% among white patients. The proportion at goal increased from 35% to 76% and from 24% to 59% among white and African American patients, respectively. African American patients were less likely to be tested for LDL-C (odds ratio [OR] 0.79; 95% confidence interval [CI] 0.73-0.86), treated with lipidlowering agents (OR 0.72; 95% CI 0.65-0.80), have their medication dosage altered (OR 0.65; 95% CI 0.59-0.73), or attain LDL-C goal (OR 0.59; 95% CI 0.56-0.63) compared with white patients., Conclusions: Although rates of LDL-C testing, treatment, and goal attainment improved over time, racial disparities in dyslipidemia management continued to exist. Further studies to determine the causes of differences in management by race are warranted.

Background: Asthma is an inflammatory condition often punctuated by episodic symptomatic worsening, and accordingly, patients with asthma might have waxing and waning adherence to controller therapy., Objective: We sought to measure changes in inhaled corticosteroid (ICS) adherence over time and to estimate the effect of this changing pattern of use on asthma exacerbations., Methods: ICS adherence was estimated from electronic prescription and fill information for 298 participants in the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity. For each patient, we calculated a moving average of ICS adherence for each day of follow-up. Asthma exacerbations were defined as the need for oral corticosteroids, an asthma-related emergency department visit, or an asthma-related hospitalization. Proportional hazard models were used to assess the relationship between ICS medication adherence and asthma exacerbations., Results: Adherence to ICS medications began to increase before the first asthma exacerbation and continued afterward. Adherence was associated with a reduction in exacerbations but was only statistically significant among patients whose adherence was greater than 75% of the prescribed dose (hazard ratio, 0.61; 95% CI, 0.41-0.90) when compared with patients whose adherence was 25% or less. This pattern was largely confined to patients whose asthma was not well controlled initially. An estimated 24% of asthma exacerbations were attributable to ICS medication nonadherence., Conclusions: ICS adherence varies in the time period leading up to and after an asthma exacerbation, and nonadherence likely contributes to a large number of these exacerbations. High levels of adherence are likely required to prevent these events., (Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Medication nonadherence is common and results in preventable disease complications. This study assessed the effectiveness of a multifactorial intervention to improve both medication adherence and blood pressure control and to reduce cardiovascular events., Methods and Results: In this multicenter, cluster-randomized trial, physicians from hospital-based hypertension clinics and primary care centers across Spain were randomized to receive and provide the intervention to their high-risk patients. Eligible patients were ≥ 50 years of age, had uncontrolled hypertension, and had an estimated 10-year cardiovascular risk greater than 30%. Physicians randomized to the intervention group counted patients' pills, designated a family member to support adherence behavior, and provided educational information to patients. The primary outcome was blood pressure control at 6 months. Secondary outcomes included both medication adherence and a composite end point of all-cause mortality and cardiovascular-related hospitalizations. Seventy-nine physicians and 877 patients participated in the trial. The mean duration of follow-up was 39 months. Intervention patients were less likely to have an uncontrolled systolic blood pressure (odds ratio 0.62, 95% confidence interval 0.50 to 0.78) and were more likely to be adherent (odds ratio 1.91, 95% confidence interval 1.19 to 3.05) than control group patients at 6 months. After 5 years, 16% of the patients in the intervention group and 19% in the control group met the composite end point (hazard ratio 0.97, 95% confidence interval 0.67 to 1.39)., Conclusions: A multifactorial intervention to improve adherence to antihypertensive medication was effective in improving both adherence and blood pressure control, but it did not appear to improve long-term cardiovascular events.

Background: Inhaled corticosteroid (ICS) nonadherence is common among patients with asthma; however, interventions to improve adherence have often been complex and not easily applied to large patient populations., Objective: To assess the effect of supplying patient adherence information to primary care providers., Methods: Patients and providers were members of a health system serving southeast Michigan. Providers (88 intervention; 105 control) and patients (1335 intervention; 1363 control) were randomized together by practice. Patients were age 5 to 56 years, had a diagnosis of asthma, and had existing prescriptions for ICS medication. Adherence was estimated by using prescription and fill data. Unlike clinicians in the control arm, intervention arm providers could view updated ICS adherence information on their patients via electronic prescription software, and further details on patient ICS use could be viewed by selecting that option. The primary outcome was ICS adherence in last 3 months of the study period., Results: At the study end for the intention-to-treat analysis, ICS adherence was not different among patients in the intervention arm compared with those in the control arm (21.3% vs 23.3%, respectively; P = .553). However, adherence was significantly higher among patients whose clinician elected to view their detailed adherence information (35.7%) compared with both control arm patients (P = .026) and intervention arm patients whose provider did not view adherence data (P = .002)., Conclusions: Overall, providing adherence information to clinicians did not improve ICS use among patients with asthma. However, patient use may improve when clinicians are sufficiently interested in adherence to view the details of this medication use., (Copyright 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Context: Thiazolidinedione (TZD) use has recently been associated with an increased risk of fractures., Objective: The aim of this study was to determine the time-dependent relationship between TZD use and fracture risk., Design: We conducted a retrospective cohort study in a large health system in southeast Michigan., Patients: PATIENTS who received care from the health system were included if they were at least 18 yr of age, had a diagnosis of diabetes, and had at least one prescription for an oral diabetes medication. These criteria identified 19,070 individuals (9,620 women and 9,450 men)., Intervention: This study compared patients treated with TZDs to patients without TZD treatment. Cox proportional hazard models were used to assess the relationship between exposure and outcomes., Main Outcome Measures: The primary outcome was the time to fracture. Secondary analyses examined the risk of fractures in subgroups defined by sex and age., Results: TZD use was associated with an increased risk of fracture in the cohort overall [adjusted hazard ratio (aHR), 1.35; 95% confidence interval (CI), 1.05-1.71] and in women (aHR, 1.57; 95% CI, 1.16-2.14), but not in men (aHR, 1.05; 95% CI, 0.70-1.58). Women more than 65 yr of age appeared to be at greatest risk for fracture (aHR, 1.72; 95% CI, 1.17-2.52). Among women, the increased fracture risk was not apparent until after 1 yr of TZD treatment., Conclusions: TZD use was associated with an increased risk for fractures in women, particularly at ages above 65 yr. Clinicians should be aware of this association when considering TZD therapy so as to appropriately manage and counsel their patients.