Standardized Mixed-Meal Tolerance and Arginine Stimulation Tests Provide Reproducible and Complementary Measures of ß-Cell Function: Results From the Foundation for the National Institutes of Health Biomarkers Consortium Investigative Series.

OBJECTIVE: Standardized, reproducible, and feasible quantification of ß-cell function (BCF) is necessary for the evaluation of interventions to improve insulin secretion and important for comparison across studies. We therefore characterized the responses to, and reproducibility of, standardized methods of in vivo BCF across different glucose tolerance states. RESEARCH DESIGN AND METHODS: Participants classified as having normal glucose tolerance (NGT; n = 23), prediabetes (PDM; n = 17), and type 2 diabetes mellitus (T2DM; n = 22) underwent two standardized mixed-meal tolerance tests (MMTT) and two standardized arginine stimulation tests (AST) in a test-retest paradigm and one frequently sampled intravenous glucose tolerance test (FSIGT). RESULTS: From the MMTT, insulin secretion in T2DM was >86% lower compared with NGT or PDM (P < 0.001). Insulin sensitivity (Si) decreased from NGT to PDM (∼50%) to T2DM (93% lower [P < 0.001]). In the AST, insulin secretory response to arginine at basal glucose and during hyperglycemia was lower in T2DM compared with NGT and PDM (>58%; all P < 0.001). FSIGT showed decreases in both insulin secretion and Si across populations (P < 0.001), although Si did not differ significantly between PDM and T2DM populations. Reproducibility was generally good for the MMTT, with intraclass correlation coefficients (ICCs) ranging from ∼0.3 to ∼0.8 depending on population and variable. Reproducibility for the AST was very good, with ICC values >0.8 across all variables and populations. CONCLUSIONS: Standardized MMTT and AST provide reproducible and complementary measures of BCF with characteristics favorable for longitudinal interventional trials use.

Integrated cardiovascular rehabilitation: how do noncardiac and polyvascular disease patients fare?

INTRODUCTION: The burden of noncommunicable disease is increasing. Preliminary evidence suggests that benefits of cardiovascular rehabilitation (CR) participation are also observed in patients with stroke and diabetes (vascular diseases [VDs]). This study compared (1) CR utilization by clinical indication; (2) sociodemographic and clinical characteristics of VD patients who participate in CR versus those who do not; and (3) change in risk factors, functional capacity, psychosocial well-being, and health behaviors from pre- to postprogram in cardiac versus VD patients who participated in CR. METHODS: This multisite study invited new CR patients to complete a survey preprogram and again 6 months later. Clinical data including risk factors and exercise test results were extracted from patients' charts at both time points. The surveys included the Duke Activity Status Index, the Godin Leisure-Time Exercise Questionnaire, the Morisky Medication Adherence Survey, and the Patient Health Questionnaire. RESULTS: Overall, 237 (84.0%) completed the pre-CR survey, and 201 (71.3%) completed the final survey. Cardiac patients (n = 104, 68.9%) were significantly more likely to complete CR than VD patients (n = 37, 54.4%; P = .039). Vascular disease patients who enrolled in CR engaged in more physical activity pre-program (P < .05). Cardiac patients who attended CR achieved significant improvements in activity status, exercise behavior, and nutrition at the posttest (P < .01 for each). Among VD patients, there were trends toward lower depressive symptoms and greater exercise in those who participated in CR by posttest. CONCLUSIONS: This study of integrated chronic disease management provides preliminary support for the benefits of CR for patients with vascular disease.

Product Quality Research Institute evaluation of cascade impactor profiles of pharmaceutical aerosols: part 2--evaluation of a method for determining equivalence.

The purpose of this article is to present the thought process, methods, and interim results of a PQRI Working Group, which was charged with evaluating the chi-square ratio test as a potential method for determining in vitro equivalence of aerodynamic particle size distribution (APSD) profiles obtained from cascade impactor measurements. Because this test was designed with the intention of being used as a tool in regulatory review of drug applications, the capability of the test to detect differences in APSD profiles correctly and consistently was evaluated in a systematic way across a designed space of possible profiles. To establish a "base line," properties of the test in the simplest case of pairs of identical profiles were studied. Next, the test's performance was studied with pairs of profiles, where some difference was simulated in a systematic way on a single deposition site using realistic product profiles. The results obtained in these studies, which are presented in detail here, suggest that the chi-square ratio test in itself is not sufficient to determine equivalence of particle size distributions. This article, therefore, introduces the proposal to combine the chi-square ratio test with a test for impactor-sized mass based on Population Bioequivalence and describes methods for evaluating discrimination capabilities of the combined test. The approaches and results described in this article elucidate some of the capabilities and limitations of the original chi-square ratio test and provide rationale for development of additional tests capable of comparing APSD profiles of pharmaceutical aerosols.

Product Quality Research Institute evaluation of cascade impactor profiles of pharmaceutical aerosols, part 1: background for a statistical method.

The purpose of this article is 2-fold: (1) to document in the public domain the considerations that led to the development of a regulatory statistical test for comparison of aerodynamic particle size distribution (APSD) of aerosolized drug formulations, which was proposed in a US Food and Drug Administration (FDA) draft guidance for industry; and (2) to explain the background and process for evaluation of that test through a working group involving scientists from the FDA, industry, academia, and the US Pharmacopeia, under the umbrella of the Product Quality Research Institute (PQRI). The article and the referenced additional statistical information posted on the PQRI Web site explain the reasoning and methods used in the development of the APSD test, which is one of the key tests required for demonstrating in vitro equivalence of orally inhaled and nasal aerosol drug products. The article also describes the process by which stakeholders with different perspectives have worked collaboratively to evaluate properties of the test by drawing on statistical models, historical and practical information, and scientific reasoning. Overall, this article provides background information to accompany the companion article's discussion of the study's methods and results.

Prophylactic implantable cardioverter-defibrillator therapy in patients with left ventricular systolic dysfunction: a pooled analysis of 10 primary prevention trials.

Strategies to decrease sudden cardiac death in patients with left ventricular systolic dysfunction are evolving. Recent clinical trials have evaluated the role of prophylactic implantable cardioverter-defibrillators (ICDs) in patients with and without additional risk stratifiers. We pooled studies comparing treatment with and without ICDs from published data and presented abstracts, irrespective of QRS duration and etiology of systolic dysfunction. On the basis of the available clinical trials, implantation of an ICD for primary prevention of death provides a 7.9% absolute mortality reduction (p = 0.003) in patients with left ventricular (LV) systolic dysfunction who were receiving optimized medical therapy. This finding was not sensitive to the exclusion of any individual trial. The ICD is an effective primary preventative measure in patients who are at risk for death; however, the application of this therapy needs to be individualized for the patient, similar to drug therapies in LV systolic dysfunction. In health care settings without unlimited resources, optimal use of this therapy will require better risk stratification methods or lowering of the initial device cost.

CCORT/CCS quality indicators for congestive heart failure care.

BACKGROUND: Quality indicators are measurement tools for assessing the structure, processes and outcomes of care. Although quality indicators have been developed in other countries, Canadian cardiovascular disease indicators do not exist. OBJECTIVE: To develop quality indicators for measuring and improving congestive heart failure (CHF) care in Canada. METHODS: An 11-member multidisciplinary national expert panel was selected from nominees from national medical organizations. Potential quality indicators were identified by a detailed search of published guidelines, randomized trials and outcomes studies. A two-step modified Delphi process was employed with an initial screening round of indicator ratings, followed by a national quality indicator panel meeting, where definitions of the indicators were developed using consensus methods. Indicators were designed to be measurable, using retrospective chart review and linking existing administrative databases. RESULTS: The case definition criterion was developed based on a discharge diagnosis of CHF (International Classification of Diseases, 9th revision [ICD-9] code 428.x), with diagnostic confirmation using clinical criteria. In total, 29 indicators and five test indicators were recommended. Process indicators included prescription for angiotensin-converting enzyme inhibitors, beta-blockers or warfarin (for atrial fibrillation) at hospital discharge. Nonpharmacological in hospital process indicators included evaluation of left ventricular function, weight measurement and selected patient education counselling instructions. Process indicators in the ambulatory setting included prescription and adherence to drug therapies and physician follow-up. Outcome indicators included mortality, readmissions and emergency visits. CONCLUSIONS: A set of Canadian quality indicators for CHF care encompassing organizational attributes, pharmacotherapy, investigations, counselling, continuity of care and disease outcomes has been developed. These quality indicators will serve as a foundation for future studies evaluating the quality of CHF care in Canada.