Background Concerns have been raised about the possibility that inhibitors of the renin-angiotensin-aldosterone system (RAAS) could predispose individuals to severe COVID-19; however, epidemiological evidence is lacking. We report the results of a case-population study done in Madrid, Spain, since the outbreak of COVID-19.Methods In this case-population study, we consecutively selected patients aged 18 years or older with a PCRconfirmed diagnosis of COVID-19 requiring admission to hospital from seven hospitals in Madrid, who had been admitted between March 1 and March 24, 2020. As a reference group, we randomly sampled ten patients per case, individually matched for age, sex, region (ie, Madrid), and date of admission to hospital (month and day; index date), from Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP), a Spanish primary health-care database, in its last available year (2018). We extracted information on comorbidities and prescriptions up to the month before index date (ie, current use) from electronic clinical records of both cases and controls. The outcome of interest was admission to hospital of patients with COVID-19. To minimise confounding by indication, the main analysis focused on assessing the association between COVID-19 requiring admission to hospital and use of RAAS inhibitors compared with use of other antihypertensive drugs. We calculated odds ratios (ORs) and 95% CIs, adjusted for age, sex, and cardiovascular comorbidities and risk factors, using conditional logistic regression. The protocol of the study was registered in the EU electronic Register of Post-Authorisation Studies, EUPAS34437.Findings We collected data for 1139 cases and 11 390 population controls. Among cases, 444 (39•0%) were female and the mean age was 69•1 years (SD 15•4), and despite being matched on sex and age, a significantly higher proportion of cases had pre-existing cardiovascular disease (OR 1•98, 95% CI 1•62-2•41) and risk factors (1•46, 1•23-1•73) than did controls. Compared with users of other antihypertensive drugs, users of RAAS inhibitors had an adjusted OR for COVID-19 requiring admission to hospital of 0•94 (95% CI 0•77-1•15). No increased risk was observed with either angiotensin-converting enzyme inhibitors (adjusted OR 0•80, 0•64-1•00) or angiotensin-receptor blockers (1•10, 0•88-1•37). Sex, age, and background cardiovascular risk did not modify the adjusted OR between use of RAAS inhibitors and COVID-19 requiring admission to hospital, whereas a decreased risk of COVID-19 requiring admission to hospital was found among patients with diabetes who were users of RAAS inhibitors (adjusted OR 0•53, 95% CI 0•34-0•80). The adjusted ORs were similar across severity degrees of COVID-19.Interpretation RAAS inhibitors do not increase the risk of COVID-19 requiring admission to hospital, including fatal cases and those admitted to intensive care units, and should not be discontinued to prevent a severe case of COVID-19.Funding Instituto de Salud Carlos III.

Medication adherence and persistence is recognized as a worldwide public health problem, particularly important in the management of chronic diseases. Nonadherence to medical plans affects every level of the population, but particularly older adults due to the high number of coexisting diseases they are affected by and the consequent polypharmacy. Chronic disease management requires a continuous psychological adaptation and behavioral reorganization. In literature, many interventions to improve medication adherence have been described for different clinical conditions, however, most interventions seem to fail in their aims. Moreover, most interventions associated with adherence improvements are not associated with improvements in other outcomes. Indeed, in the last decades, the degree of nonadherence remained unchanged. In this work, we review the most frequent interventions employed to increase the degree of medication adherence, the measured outcomes, and the improvements achieved, as well as the main limitations of the available studies on adherence, with a particular focus on older persons.

Background Type 2 diabetes, a highly prevalent chronic disease, is associated with increasing frailty and functional decline in older people. We aimed to evaluate the effectiveness of a multimodal intervention on functional performance in frail and pre‐frail participants aged ≥70 years with type 2 diabetes mellitus. Methods The MID‐Frail study was a cluster‐randomized multicenter clinical trial conducted in 74 trial sites across seven European countries. The trial recruited 964 participants who were aged >70 years [mean age in intervention group, 78.4 (SD 5.6) years, 49.2% male and 77.6 (SD 5.29) years, 52.4% male in usual care group], with type diabetes mellitus and determined to be frail or pre‐frail using Fried's frailty phenotype. Participants were allocated by trial site to follow either usual care (UCG) or intervention procedures (IG). Intervention group participants received a multimodal intervention composed of (i) an individualized and progressive resistance exercise programme for 16 weeks; (ii) a structured diabetes and nutritional educational programme over seven sessions; and (iii) Investigator‐linked training to ensure optimal diabetes care. Short Physical Performance Battery (SPPB) scores were used to assess change in functional performance at 12 months between the groups. An analysis of the cost‐effectiveness of the intervention was undertaken using the incremental cost‐effectiveness ratio (ICER). Secondary outcomes included mortality, hospitalization, institutionalization, quality of life, burden on caregivers, the frequency and severity of hypoglycaemia episodes, and the cost‐effectiveness of the intervention. Results After 12 months, IG participants had mean SPPB scores 0.85 points higher than those in the UCG (95% CI, 0.44 to 1.26, P < 0.0001). Dropouts were higher in frail participants and in the intervention group, but significant differences in SPPB between treatment groups remained consistent after sensitivity analysis. Estimates suggest a mean saving following intervention of 428.02 EUR (2016) per patient per year, with ICER analysis indicating a consistent benefit of the described health care intervention over usual care. No statistically significant differences between groups were detected in any of the other secondary outcomes. Conclusions We have demonstrated that a 12 month structured multimodal intervention programme across several clinical settings in different European countries leads to a clinically relevant and cost‐effective improvement in the functional status of older frail and pre‐frail participants with type 2 diabetes mellitus.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • In USA and Europe the classical way to guarantee equivalence between different formulations is the bioequivalence (BE) study based on in vivo bioavailability. • The Biopharmaceutic Classification System (BCS) classifies active substances into four different groups according to their aqueous solubility and intestinal permeability. • Recently the European Medicines Agency (EMA) has released a new bioequivalence guideline for immediate release solid oral dosage forms that includes recommendations on BCS‐based biowaivers. WHAT THIS STUDY ADDS • As far as we know this is the first time that the probability of proving BE of more than one hundred BE studies with 80 active substances categorized according to BCS was evaluated. • Despite the usually employed test dissolution methodology proposed as quality control, pharmaceutical products with active substances from the four classes of BCS showed non‐BE studies. AIM The aim of this study was to evaluate the acceptability of 124 bioequivalence (BE) studies with 80 active substances categorized according to the Biopharmaceutics Classification System (BCS) in order to establish if there were different probabilities of proving BE between the different BCS classes. METHODS We evaluated the differences between pharmaceutical products with active substances from different BCS classes in terms of acceptability, number of subjects in the study (n), the point estimates, and intra‐ and inter‐subject coefficients of variation data from BE studies with generic products. RESULTS Out of 124 BE studies 89 (71.77%) were performed with pharmaceutical products containing active substances classified by the BCS. In all BCS classes there were non‐bioequivalent pharmaceutical products: 4 out of 26 (15.38%) in class 1, 14 out of 28 (50%) in class 2, 3 out of 22 (13.63%) in class 3 and 1 out of 13 (7.69%) in class 4. When we removed those pharmaceutical products in which intra‐subject variability was higher than predicted (2 in class 1 active substances, 9 in class 2 and 2 in class 3) there were still non‐BE pharmaceutical products in classes 1, 2 and 3. CONCLUSIONS Comparisons between pharmaceutical products with active substances from the four BCS classes have not allowed us to define differential characteristics of each class in terms of n, inter and intra‐subject variability for Cmax or AUC. Despite the usually employed test dissolution methodology proposed as quality control, pharmaceutical products with active substances from the four classes of BCS showed non‐BE studies.

Several immunomodulatory agents are used in the treatment of epidermal necrolysis, but evidence of their efficacy is limited. The Autonomous Community of Madrid has two reference burn units to which all patients with epidermal necrolysis are referred. One burn unit has mostly used cyclosporine (CsA), and the other has used non-CsA therapies (mainly high-dose intravenous immunoglobulin). The allocation of patients to one or the other burn unit was mainly based on proximity, resembling a random assignment. Thus, we took advantage of this "natural experiment" to estimate the mortality risk ratio (MRR) of CsA (n = 26) compared with non-CsA (n = 16) treatment using hospital as an instrumental variable over the period from 2001 to 2015. We also computed the observed versus expected (O/E) MRR in a case series of 49 CsA-treated patients (including 23 patients from other regions treated in Madrid), and using the Score for Toxic Epidermal Necrolysis (i.e., SCORTEN) scale to estimate the expected values. The instrumental variable-based MRR of CsA versus non-CsA was 0.09 (95% confidence interval = 0.00-0.49). The O/E analysis also showed a reduction in mortality risk (MRR = 0.42; 95% confidence interval = 0.14-0.99). We identified five other case series of CsA-treated patients providing MRR and meta-analyzed their results. The pooled MRR (including from this study) was 0.41 (95% confidence interval = 0.21-0.80). All three approaches consistently show that CsA reduces the mortality in epidermal necrolysis patients.

Objective To evaluate the role of functional status along with other used clinical factors on the occurrence of death in patients hospitalized with COVID-19. Design Prospective Cohort study Setting Public University Hospital (Madrid) Participants and methods 375 consecutive patients with COVID-19 infection, admitted to a Public University Hospital (Madrid) between March 1 and March 31, 2020, were included in the Prospective Cohort study. Death was the main outcome. The main variable was disability in Activities of Daily Living (ADL) assessed with the Barthel index. Covariates included sex, age, severity index (Quick Sequential Organ Failure Assessment, qSOFA), polypharmacy (>5 drugs in the month before admission), and comorbidity (≥3 diseases). Multivariable logistic regression was used to identify risk factors for adverse outcomes. Estimated model coefficients served to calculate the expected probability of death for a selected combination of five variables: Barthel, sex, age, comorbidities and severity index (qSOFA). Results Mean age was 66 years (SD 15.33), 207 (55%) males. 74 patients died (19.8%). Mortality was associated to low Barthel index (OR per 5-point decrease 1.11; 95CI 1.03-1.20), male sex (0.23, 0.11-0.47), age (1.07, 1.03-1.10) and comorbidity (2.15; 1.08-4.30) but not to qSOFA (1.29, 0.87-1.93) or polypharmacy (1.54; 0.77-3.08). Calculated mortality risk ranged from 0 to 0.78. Conclusions and implications Functional status predicts death in hospitalized COVID-19 patients. Combination of five variables allows to predict individual probability of death. These findings provide useful information for the decision-making process and management of patients.

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