Statistical Considerations for Embedded Pragmatic Clinical Trials in People Living with Dementia

There is overwhelming need for nonpharmacological interventions to improve the health and well-being of people living with dementia (PLWD). The National Institute on Aging Imbedded Pragmatic Alzheimer's Disease (AD) and AD-Related Dementias Clinical Trials (IMPACT) Collaboratory supports clinical trials of such interventions embedded in healthcare systems. The embedded pragmatic clinical trial (ePCT) is ideally suited to testing the effectiveness of complex interventions in vulnerable populations at the point of care. These trials, however, are complex to conduct and interpret, and face challenges in efficiency (i.e., statistical power) and reproducibility. In addition, trials conducted among PLWD present specific statistical challenges, including difficulty in outcomes ascertainment from PLWD, necessitating reliance on reports by caregivers, and heterogeneity in measurements across different settings or populations. These and other challenges undercut the reliability of measurement, the feasibility of capturing outcomes using pragmatic designs, and the ability to validly estimate interventions' effectiveness in real-world settings. To address these challenges, the IMPACT Collaboratory has convened a Design and Statistics Core, the goals of which are: to support the design and conduct of ePCTs directed toward PLWD and their caregivers; to develop guidance for conducting embedded trials in this population; and to educate quantitative and clinical scientists in the design, conduct, and analysis of these trials. In this article, we discuss some of the contemporary methodological challenges in this area and develop a set of research priorities the Design and Statistics Core will undertake to meet these goals. J Am Geriatr Soc 68:S68–S73, 2020 .     

Effects of Spironolactone Treatment in Elderly Women With Heart Failure and Preserved Left Ventricular Ejection Fraction

BackgroundAlthough spironolactone has been shown to decrease morbidity and mortality in patients with heart failure and reduced left ventricular ejection fraction, its role in patients with heart failure and preserved left ventricular ejection fraction (HFpEF) is not well defined. In this study we investigated the mechanisms involved when elderly women with HFpEF are treated with spironolactone.Methods and ResultsForty-eight women with HFpEF were enrolled in a randomized placebo-controlled trial and were assigned to 25 mg spironolactone daily (n = 24) or placebo (n = 24) for 6 months. Six-minute walk distance, clinical composite score, Doppler echocardiography, and biomarkers were determined at baseline and after 3 and 6 months of therapy. Six months of spironolactone treatment stabilized clinical symptoms, as demonstrated by significant worsening of the clinical composite score in the placebo group (P = .02). In addition, spironolactone treatment improved diastolic function by significantly increasing early diastolic tissue Doppler velocity of the lateral mitral annulus (lateral e′; P = .003) and significantly reducing the mitral peak E velocity to lateral e′ ratio (lateral E/e′; P = .0001). Finally, spironolactone favorably affected remodeling through a reduction in myocardial fibrosis measured by a reduction in type III procollagen levels (P = .035). Six-minute walk distance did not significantly improve with spironolactone treatment compared with placebo.ConclusionsSpironolactone stabilizes functional capacity and symptoms and improves diastolic function, possibly through its ability to suppress type III procollagen synthesis.     

Quantitative Estimation of Plasma Free Drug Fraction in Patients With Varying Degrees of Hepatic Impairment: A Methodological Evaluation

Quantitative prediction of unbound drug fraction (f_u) is essential for scaling pharmacokinetics through physiologically based approaches. However, few attempts have been made to evaluate the projection of f_u values under pathological conditions. The primary objective of this study was to predict f_u values (n = 105) of 56 compounds with or without the information of predominant binding protein in patients with varying degrees of hepatic insufficiency by accounting for quantitative changes in molar concentrations of either the major binding protein or albumin plus alpha 1-acid glycoprotein associated with differing levels of hepatic dysfunction. For the purpose of scaling, data pertaining to albumin and α1-acid glycoprotein levels in response to differing degrees of hepatic impairment were systematically collected from 919 adult donors. The results of the present study demonstrate for the first time the feasibility of physiologically based scaling f_u in hepatic dysfunction after verifying with experimentally measured data of a wide variety of compounds from individuals with varying degrees of hepatic insufficiency. Furthermore, the high level of predictive accuracy indicates that the inter-relation between the severity of hepatic impairment and these plasma protein levels are physiologically accurate. The present study enhances the confidence in predicting f_u in hepatic insufficiency, particularly for albumin-bound drugs.     

Vinylsiloxanether: A New Impression Material. Clinical Study of Implant Impressions with Vinylsiloxanether versus Polyether Materials

Aim: The performance of three elastomeric materials for the open monophase implant impressions technique was tested under the following clinical conditions: polyether (IM) and vinylsiloxanether without (ID) and with additional simultaneous splinting of the implant impression copings with a higher shore hardness A‐silicone (IDF). Materials and Methods: The three test groups, IM, ID, and IDF, were randomly allocated 10 test subjects with three to five implants each. The impressions were analyzed regarding the subjective clinical assessments with 11‐point rating scales by the dentist, the patient, and the dental technician, as well as to the comparison of these assessments with the objectified clinical fit of the manufactured crowns based on standard clinical evaluation criteria. The three groups were statistically analyzed on the basis of the hypothesis of non‐inferiority of ID versus IM and IDF versus IM (alpha < 0.05). Results: The results of the study showed the objective clinical fit of the dental prostheses made using ID being comparable to the results obtained with IM. Compared with ID and IM, the precision of fit attained with IDF was reduced, although the subjective dentist assessments of IDF were in parts significantly better than those of IM and ID (p = .015). A statistically significant superiority of ID in comparison with IM could be determined with regard to the subjective ratings of the taste by the test subject (p < .01), of the handling (p < .001) and of the precision details of impression (p = .012) by the dentist, and of removing the plaster model from the mold by the dental technician (p = .017). Conclusions: The overall results of the vinylsiloxanether material in terms of the patients', dentists', and dental technicians' assessments proved to be equivalent or superior to those of the polyether material. The IDF technique cannot be recommended for this application.