Mental health and risk of death and hospitalization in COVID-19 patients. Results from a large-scale population-based study in Spain.

The COVID-19 pandemic has created unprecedented challenges for health care systems globally. This study aimed to explore the presence of mental illness in a Spanish cohort of COVID-19-infected population and to evaluate the association between the presence of specific mental health conditions and the risk of death and hospitalization. This is a retrospective cohort study including all individuals with confirmed infection by SARS-CoV-2 from the PRECOVID (Prediction in COVID-19) Study (Aragon, Spain). Mental health illness was defined as the presence of schizophrenia and other psychotic disorders, anxiety, cognitive disorders, depression and mood disorders, substance abuse, and personality and eating disorders. Multivariable logistic regression models were used to examine the likelihood of 30-day all-cause mortality and COVID-19 related hospitalization based on baseline demographic and clinical variables, including the presence of specific mental conditions, by gender. We included 144,957 individuals with confirmed COVID-19 from the PRECOVID Study (Aragon, Spain). The most frequent diagnosis in this cohort was anxiety. However, some differences were observed by sex: substance abuse, personality disorders and schizophrenia were more frequently diagnosed in men, while eating disorders, depression and mood, anxiety and cognitive disorders were more common among women. The presence of mental illness, specifically schizophrenia spectrum and cognitive disorders in men, and depression and mood disorders, substance abuse, anxiety and cognitive and personality disorders in women, increased the risk of mortality or hospitalization after COVID-19, in addition to other well-known risk factors such as age, morbidity and treatment burden. Identifying vulnerable patient profiles at risk of serious outcomes after COVID-19 based on their mental health status will be crucial to improve their access to the healthcare system and the establishment of public health prevention measures for future outbreaks.

Drug Repurposing in Oncology: A Systematic Review of Randomized Controlled Clinical Trials.

Quality pharmacological treatment can improve survival in many types of cancer. Drug repurposing offers advantages in comparison with traditional drug development procedures, reducing time and risk. This systematic review identified the most recent randomized controlled clinical trials that focus on drug repurposing in oncology. We found that only a few clinical trials were placebo-controlled or standard-of-care-alone-controlled. Metformin has been studied for potential use in various types of cancer, including prostate, lung, and pancreatic cancer. Other studies assessed the possible use of the antiparasitic agent mebendazole in colorectal cancer and of propranolol in multiple myeloma or, when combined with etodolac, in breast cancer. We were able to identify trials that study the potential use of known antineoplastics in other non-oncological conditions, such as imatinib for severe coronavirus disease in 2019 or a study protocol aiming to assess the possible repurposing of leuprolide for Alzheimer's disease. Major limitations of these clinical trials were the small sample size, the high clinical heterogeneity of the participants regarding the stage of the neoplastic disease, and the lack of accounting for multimorbidity and other baseline clinical characteristics. Drug repurposing possibilities in oncology must be carefully examined with well-designed trials, considering factors that could influence prognosis.

Multimorbidity Clusters in the Oldest Old: Results from the EpiChron Cohort.

Multimorbidity is challenging for both patients and healthcare systems due to its increasing prevalence and high impact on people's health and well-being. The risk of multimorbidity increases with age, but there is still more to discover regarding the clinical profile of the oldest old. In this study, we used information from the EpiChron Cohort Study to identify multimorbidity patterns in individuals who died during the period 2010-2019 at the ages of 80-89, 90-99, and ≥100. This cohort links the demographic, clinical, and drug dispensation information of public health system users in Aragón, Spain. We saw a significantly lower number of chronic diseases and drugs and a lower prevalence of polypharmacy in centenarians compared to those aged 80-99. K-means clustering revealed different multimorbidity clusters by sex and age group. We observed clusters of cardiovascular and metabolic diseases, obstructive pulmonary conditions, and neoplasms, amongst other profiles. One in three octogenarian women had a metabolic pattern (diabetes, dyslipidaemia, and other endocrine-metabolic disorders) with the highest number of diseases (up to seven) and prevalence of polypharmacy (64%). We observed clusters of dementia and genitourinary disorders in individuals on medication with anticholinergic activity. Our study offers an opportunity to better understand the urgency of adequately addressing multimorbidity in our older adults.

Effectiveness of the MULTIPAP Plus intervention in youngest-old patients with multimorbidity and polypharmacy aimed at improving prescribing practices in primary care: study protocol of a cluster randomized trial.

BACKGROUND: The progressive ageing of the population is leading to an increase in multimorbidity and polypharmacy, which in turn may increase the risk of hospitalization and mortality. The enhancement of care with information and communications technology (ICT) can facilitate the use of prescription evaluation tools and support system for decision-making (DSS) with the potential of optimizing the healthcare delivery process. OBJECTIVE: To assess the effectiveness and cost-effectiveness of the complex intervention MULTIPAP Plus, compared to usual care, in improving prescriptions for young-old patients (65-74 years old) with multimorbidity and polypharmacy in primary care. METHODS/DESIGN: This is a pragmatic cluster-randomized clinical trial with a follow-up of 18 months in health centres of the Spanish National Health System. Unit of randomization: family physician. Unit of analysis: patient. POPULATION: Patients aged 65-74 years with multimorbidity (≥ 3 chronic diseases) and polypharmacy (≥ 5 drugs) during the previous 3 months were included. SAMPLE SIZE: n = 1148 patients (574 per study arm). INTERVENTION: Complex intervention based on the ARIADNE principles with three components: (1) family physician (FP) training, (2) FP-patient interview, and (3) decision-making support system. OUTCOMES: The primary outcome is a composite endpoint of hospital admission or death during the observation period measured as a binary outcome, and the secondary outcomes are number of hospital admission, all-cause mortality, use of health services, quality of life (EQ-5D-5L), functionality (WHODAS), falls, hip fractures, prescriptions and adherence to treatment. Clinical and sociodemographic factors will be explanatory variables. STATISTICAL ANALYSIS: The main result is the difference in percentages in the final composite endpoint variable at 18 months, with its corresponding 95% CI. Adjustments by the main confounding and prognostic factors will be performed through a multilevel analysis. All analyses will be carried out in accordance to the intention-to-treat principle. DISCUSSION: It is important to prevent the cascade of negative health and health care impacts attributable to the multimorbidity-polypharmacy binomial. ICT-enhanced routine clinical practice could improve the prescription process in patient care. TRIAL REGISTRATION: ClinicalTrials.gov NCT04147130 . Registered on 22 October 2019.

How to Improve Healthcare for Patients with Multimorbidity and Polypharmacy in Primary Care: A Pragmatic Cluster-Randomized Clinical Trial of the MULTIPAP Intervention.

(1) Purpose: To investigate a complex MULTIPAP intervention that implements the Ariadne principles in a primary care population of young-elderly patients with multimorbidity and polypharmacy and to evaluate its effectiveness for improving the appropriateness of prescriptions. (2) Methods: A pragmatic cluster-randomized clinical trial was conducted involving 38 family practices in Spain. Patients aged 65-74 years with multimorbidity and polypharmacy were recruited. Family physicians (FPs) were randomly allocated to continue usual care or to provide the MULTIPAP intervention based on the Ariadne principles with two components: FP training (eMULTIPAP) and FP patient interviews. The primary outcome was the appropriateness of prescribing, measured as the between-group difference in the mean Medication Appropriateness Index (MAI) score change from the baseline to the 6-month follow-up. The secondary outcomes were quality of life (EQ-5D-5 L), patient perceptions of shared decision making (collaboRATE), use of health services, treatment adherence, and incidence of drug adverse events (all at 1 year), using multi-level regression models, with FP as a random effect. (3) Results: We recruited 117 FPs and 593 of their patients. In the intention-to-treat analysis, the between-group difference for the mean MAI score change after a 6-month follow-up was -2.42 (95% CI from -4.27 to -0.59) and, between baseline and a 12-month follow-up was -3.40 (95% CI from -5.45 to -1.34). There were no significant differences in any other secondary outcomes. (4) Conclusions: The MULTIPAP intervention improved medication appropriateness sustainably over the follow-up time. The small magnitude of the effect, however, advises caution in the interpretation of the results given the paucity of evidence for the clinical benefit of the observed change in the MAI. Trial registration: Clinicaltrials.gov NCT02866799.

Multimorbidity Profiles and Infection Severity in COVID-19 Population Using Network Analysis in the Andalusian Health Population Database.

Identifying the population at risk of COVID-19 infection severity is a priority for clinicians and health systems. Most studies to date have only focused on the effect of specific disorders on infection severity, without considering that patients usually present multiple chronic diseases and that these conditions tend to group together in the form of multimorbidity patterns. In this large-scale epidemiological study, including primary and hospital care information of 166,242 patients with confirmed COVID-19 infection from the Spanish region of Andalusia, we applied network analysis to identify multimorbidity profiles and analyze their impact on the risk of hospitalization and mortality. Our results showed that multimorbidity was a risk factor for COVID-19 severity and that this risk increased with the morbidity burden. Individuals with advanced cardio-metabolic profiles frequently presented the highest infection severity risk in both sexes. The pattern with the highest severity associated in men was present in almost 28.7% of those aged ≥ 80 years and included associations between cardiovascular, respiratory, and metabolic diseases; age-adjusted odds ratio (OR) 95% confidence interval (1.71 (1.44-2.02)). In women, similar patterns were also associated the most with infection severity, in 7% of 65-79-year-olds (1.44 (1.34-1.54)) and in 29% of ≥80-year-olds (1.35 (1.18-1.53)). Patients with mental health patterns also showed one of the highest risks of COVID-19 severity, especially in women. These findings strongly recommend the implementation of personalized approaches to patients with multimorbidity and SARS-CoV-2 infection, especially in the population with high morbidity burden.

Identifying multimorbidity profiles associated with COVID-19 severity in chronic patients using network analysis in the PRECOVID Study.

A major risk factor of COVID-19 severity is the patient's health status at the time of the infection. Numerous studies focused on specific chronic diseases and identified conditions, mainly cardiovascular ones, associated with poor prognosis. However, chronic diseases tend to cluster into patterns, each with its particular repercussions on the clinical outcome of infected patients. Network analysis in our population revealed that not all cardiovascular patterns have the same risk of COVID-19 hospitalization or mortality and that this risk depends on the pattern of multimorbidity, besides age and sex. We evidenced that negative outcomes were strongly related to patterns in which diabetes and obesity stood out in older women and men, respectively. In younger adults, anxiety was another disease that increased the risk of severity, most notably when combined with menstrual disorders in women or atopic dermatitis in men. These results have relevant implications for organizational, preventive, and clinical actions to help meet the needs of COVID-19 patients.

Chronic diseases associated with increased likelihood of hospitalization and mortality in 68,913 COVID-19 confirmed cases in Spain: A population-based cohort study.

BACKGROUND: Clinical outcomes among COVID-19 patients vary greatly with age and underlying comorbidities. We aimed to determine the demographic and clinical factors, particularly baseline chronic conditions, associated with an increased risk of severity in COVID-19 patients from a population-based perspective and using data from electronic health records (EHR). METHODS: Retrospective, observational study in an open cohort analyzing all 68,913 individuals (mean age 44.4 years, 53.2% women) with SARS-CoV-2 infection between 15 June and 19 December 2020 using exhaustive electronic health registries. Patients were followed for 30 days from inclusion or until the date of death within that period. We performed multivariate logistic regression to analyze the association between each chronic disease and severe infection, based on hospitalization and all-cause mortality. RESULTS: 5885 (8.5%) individuals showed severe infection and old age was the most influencing factor. Congestive heart failure (odds ratio -OR- men: 1.28, OR women: 1.39), diabetes (1.37, 1.24), chronic renal failure (1.31, 1.22) and obesity (1.21, 1.26) increased the likelihood of severe infection in both sexes. Chronic skin ulcers (1.32), acute cerebrovascular disease (1.34), chronic obstructive pulmonary disease (1.21), urinary incontinence (1.17) and neoplasms (1.26) in men, and infertility (1.87), obstructive sleep apnea (1.43), hepatic steatosis (1.43), rheumatoid arthritis (1.39) and menstrual disorders (1.18) in women were also associated with more severe outcomes. CONCLUSIONS: Age and specific cardiovascular and metabolic diseases increased the risk of severe SARS-CoV-2 infections in men and women, whereas the effects of certain comorbidities are sex specific. Future studies in different settings are encouraged to analyze which profiles of chronic patients are at higher risk of poor prognosis and should therefore be the targets of prevention and shielding strategies.

Baseline Drug Treatments as Indicators of Increased Risk of COVID-19 Mortality in Spain and Italy.

This study aims to identify baseline medications that, as a proxy for the diseases they are dispensed for, are associated with increased risk of mortality in COVID-19 patients from two regions in Spain and Italy using real-world data. We conducted a cross-country, retrospective, observational study including 8570 individuals from both regions with confirmed SARS-CoV-2 infection between 4 March and 17 April 2020, and followed them for a minimum of 30 days to allow sufficient time for the studied event, in this case death, to occur. Baseline demographic variables and all drugs dispensed in community pharmacies three months prior to infection were extracted from the PRECOVID Study cohort (Aragon, Spain) and the Campania Region Database (Campania, Italy) and analyzed using logistic regression models. Results show that the presence at baseline of potassium-sparing agents, antipsychotics, vasodilators, high-ceiling diuretics, antithrombotic agents, vitamin B12, folic acid, and antiepileptics were systematically associated with mortality in COVID-19 patients from both countries. Treatments for chronic cardiovascular and metabolic diseases, systemic inflammation, and processes with increased risk of thrombosis as proxies for the conditions they are intended for can serve as timely indicators of an increased likelihood of mortality after the infection, and the assessment of pharmacological profiles can be an additional approach to the identification of at-risk individuals in clinical practice.

Drug Prescription Profiles in Patients with Polypharmacy in Spain: A Large-Scale Pharmacoepidemiologic Study Using Real-World Data.

We aimed to identify and compare medication profiles in populations with polypharmacy between 2005 and 2015. We conducted a cross-sectional study using information from the Computerized Database for Pharmacoepidemiologic Studies in Primary Care (BIFAP, Spain). We estimated the prevalence of therapeutic subgroups in all individuals 15 years of age and older with polypharmacy (≥5 drugs during ≥6 months) using the Anatomical Therapeutic Chemical classification system level 4, by sex and age group, for both calendar years. The most prescribed drugs were proton-pump inhibitors (PPIs), statins, antiplatelet agents, benzodiazepine derivatives, and angiotensin-converting enzyme inhibitors. The greatest increases between 2005 and 2015 were observed in PPIs, statins, other antidepressants, and ß-blockers, while the prevalence of antiepileptics was almost tripled. We observed increases in psychotropic drugs in women and cardiovascular medications in men. By patient´s age groups, there were notable increases in antipsychotics, antidepressants, and antiepileptics (15-44 years); antidepressants, PPIs, and selective ß-blockers (45-64 years); selective ß-blockers, biguanides, PPIs, and statins (65-79 years); and in statins, selective ß-blockers, and PPIs (80 years and older). Our results revealed important increases in the use of specific therapeutic subgroups, like PPIs, statins, and psychotropic drugs, highlighting opportunities to design and implement strategies to analyze such prescriptions' appropriateness.

Changes in Multimorbidity and Polypharmacy Patterns in Young and Adult Population over a 4-Year Period: A 2011-2015 Comparison Using Real-World Data.

The pressing problem of multimorbidity and polypharmacy is aggravated by the lack of specific care models for this population. We aimed to investigate the evolution of multimorbidity and polypharmacy patterns in a given population over a 4-year period (2011-2015). A cross-sectional, observational study among the EpiChron Cohort, including anonymized demographic, clinical and drug dispensation information of all users of the public health system ≥65 years in Aragon (Spain), was performed. An exploratory factor analysis, stratified by age and sex, using an open cohort was carried out based on the tetra-choric correlations among chronic diseases and dispensed drugs during 2011 and compared with 2015. Seven baseline patterns were identified during 2011 named as: mental health, respiratory, allergic, mechanical pain, cardiometabolic, osteometabolic, and allergic/derma. Of the epidemiological patterns identified in 2015, six were already present in 2011 but a new allergic/derma one appeared. Patterns identified in 2011 were more complex in terms of both disease and drugs. Results confirmed the existing association between age and clinical complexity. The systematic associations between diseases and drugs remain similar regarding their clinical nature over time, helping in early identification of potential interactions in multimorbid patients with a high risk of negative health outcomes due to polypharmacy.

Multimorbidity clusters in patients with chronic obstructive airway diseases in the EpiChron Cohort.

Chronic obstructive airway diseases such as chronic obstructive pulmonary disease (COPD), asthma, rhinitis, and obstructive sleep apnea (OSA) are amongst the most common treatable and preventable chronic conditions with high morbidity burden and mortality risk. We aimed to explore the existence of multimorbidity clusters in patients with such diseases and to estimate their prevalence and impact on mortality. We conducted an observational retrospective study in the EpiChron Cohort (Aragon, Spain), selecting all patients with a diagnosis of allergic rhinitis, asthma, COPD, and/or OSA. The study population was stratified by age (i.e., 15-44, 45-64, and ≥ 65 years) and gender. We performed cluster analysis, including all chronic conditions recorded in primary care electronic health records and hospital discharge reports. More than 75% of the patients had multimorbidity (co-existence of two or more chronic conditions). We identified associations of dermatologic diseases with musculoskeletal disorders and anxiety, cardiometabolic diseases with mental health problems, and substance use disorders with neurologic diseases and neoplasms, amongst others. The number and complexity of the multimorbidity clusters increased with age in both genders. The cluster with the highest likelihood of mortality was identified in men aged 45 to 64 years and included associations between substance use disorder, neurologic conditions, and cancer. Large-scale epidemiological studies like ours could be useful when planning healthcare interventions targeting patients with chronic obstructive airway diseases and multimorbidity.

Baseline Chronic Comorbidity and Mortality in Laboratory-Confirmed COVID-19 Cases: Results from the PRECOVID Study in Spain.

We aimed to analyze baseline socio-demographic and clinical factors associated with an increased likelihood of mortality in men and women with coronavirus disease (COVID-19). We conducted a retrospective cohort study (PRECOVID Study) on all 4412 individuals with laboratory-confirmed COVID-19 in Aragon, Spain, and followed them for at least 30 days from cohort entry. We described the socio-demographic and clinical characteristics of all patients of the cohort. Age-adjusted logistic regressions models were performed to analyze the likelihood of mortality based on demographic and clinical variables. All analyses were stratified by sex. Old age, specific diseases such as diabetes, acute myocardial infarction, or congestive heart failure, and dispensation of drugs like vasodilators, antipsychotics, and potassium-sparing agents were associated with an increased likelihood of mortality. Our findings suggest that specific comorbidities, mainly of cardiovascular nature, and medications at the time of infection could explain around one quarter of the mortality in COVID-19 disease, and that women and men probably share similar but not identical risk factors. Nonetheless, the great part of mortality seems to be explained by other patient- and/or health-system-related factors. More research is needed in this field to provide the necessary evidence for the development of early identification strategies for patients at higher risk of adverse outcomes.

Multimorbidity Patterns in the General Population: Results from the EpiChron Cohort Study.

The correct management of patients with multimorbidity remains one of the main challenges for healthcare systems worldwide. In this study, we analyze the existence of multimorbidity patterns in the general population based on gender and age. We conducted a cross-sectional study of individuals of all ages from the EpiChron Cohort, Spain (1,253,292 subjects), and analyzed the presence of systematic associations among chronic disease diagnoses using exploratory factor analysis. We identified and clinically described a total of 14 different multimorbidity patterns (12 in women and 12 in men), with some relevant differences in the functions of age and gender. The number and complexity of the patterns was shown to increase with age in both genders. We identified associations of circulatory diseases with respiratory disorders, chronic musculoskeletal diseases with depression and anxiety, and a very consistent pattern of conditions whose co-occurrence is known as metabolic syndrome (hypertension, diabetes, obesity, and dyslipidaemia), among others. Our results demonstrate the potential of using real-world data to conduct large-scale epidemiological studies to assess the complex interactions among chronic conditions. This could be useful in designing clinical interventions for patients with multimorbidity, as well as recommendations for healthcare professionals on how to handle these types of patients in clinical practice.

MULTIPAP Study: Improving healthcare for patients with multimorbidity.

BACKGROUND: The steady rise in multimorbidity entails serious consequences for our populations, challenges healthcare systems, and calls for specific clinical approaches of proven effectiveness. The MULTIPAP Study comprises three sequential projects (MULTIPAP and MULTIPAP Plus RCTs, and the MULTIPAP Cohort). Results of MULTIPAP RCT are presented. AIM: To evaluate the effectiveness of a complex, patient-centred intervention in young-old patients with multimorbidity and polypharmacy. METHOD: Pragmatic cluster-randomised clinical trial in a primary healthcare setting. GPs were randomly allocated to either conventional care or the MULTIPAP intervention based on the Ariadne Principles with two components: GPs e-training (that is, eMULTIPAP addresses specific, key concepts on multimorbidity, polypharmacy and shared decision-making) and GP-patient-centred interview. Young-old patients aged 65-74 years with multimorbidity and polypharmacy were included. MAIN OUTCOME: difference in the Medication Appropriateness Index (MAI) after 6-month follow-up between groups. SECONDARY OUTCOMES: MAI, quality of life, patient perception, health services use, treatment adherence and cost-effectiveness after 12-month follow-up. RESULTS: 117 GPs from 38 Spanish primary health care recruited 593 patients randomly assigned to the intervention/control groups. Difference in MAI scores between groups in the intention-to-treat analysis after 6 months' follow-up: -2.42 (-4.27 to -0.59), P = 0.009 (adjusted difference in mean MAI score -1.81(-3.35 to -0.27), P = 0.021). SECONDARY OUTCOMES: not significant, including quality of life (adjusted difference in mean EQ-5D-5L (VAS) 2.94 (-1.39 to 7.28), P = 0.183, EQ-5D-5L (index) -0.006(-0.034 to 0.022), P = 0.689). CONCLUSION: The intervention significantly improved medication appropriateness. The observed quality of life improvement was not significant. GPs e-training in multimorbidity has shown to be feasible and well accepted by the professionals. Future studies may test whether this format facilitates implementation.

Do Centenarians Die Healthier than Younger Elders? A Comparative Epidemiological Study in Spain.

This study aims to describe the clinical course, drug use, and health services use characteristics during the last year of life of elders who die being centenarians and to identify key aspects differentiating them from elders who die at an earlier age, with a particular focus on sex differences. We conducted an observational, population-based study in the EpiChron Cohort (Aragón, Spain). The population was stratified by sex and into three age sub-populations (80-89, 90-99, and ≥100 years), and their characteristics were described and compared. Multimorbidity was the rule in our elders, affecting up to 3 in 4 centenarians and 9 in 10 octogenarians and nonagenarians. Polypharmacy was also observed in half of the centenarian population and in most of the younger elders. Risk factors for cardiovascular disease (i.e., hypertension, dyslipidaemia, diabetes), cerebrovascular disease and dementia were amongst the most common chronic conditions in all age groups, whereas the gastroprotective drugs and antithrombotic agents were the most dispensed drugs. Centenarians presented in general lower morbidity and treatment burden and lower use of both primary and hospital healthcare services than octogenarians and nonagenarians, suggesting a better health status. Sex-differences in their clinical characteristics were more striking in octogenarians and tended to decrease with age.

Initial Therapy, Regimen Change, and Persistence in a Spanish Cohort of Newly Treated Type 2 Diabetes Patients: A Retrospective, Observational Study Using Real-World Data.

The World Health Organization considers the non-adherence to medication a significant issue with global impact, especially in chronic conditions such as type 2 diabetes. We aim to study antidiabetic treatment initiation, add-on, treatment switching, and medication persistence. We conducted an observational study on 4247 individuals initiating antidiabetic treatment between 2013 and 2014 in the EpiChron Cohort (Spain). We used Cox regression models to estimate the likelihood of non-persistence after a one-year follow-up, expressed as hazard ratios (HRs). Metformin was the most frequently used first-line antidiabetic (80% of cases); combination treatment was the second most common treatment in adults aged 40-79 years, while dipeptidyl peptidase-4 inhibitors were the second most common in individuals in their 80s and over, and in patients with renal disease. Individuals initiated on metformin were less likely to present addition and switching events compared with any other antidiabetic. Almost 70% of individuals initiated on monotherapy were persistent. Subjects aged 40 and over (HR 0.53-0.63), living in rural (HR 0.79) or more deprived areas (HR 0.77-0.82), or receiving polypharmacy (HR 0.84), were less likely to show discontinuation. Our findings could help identify the population at risk of discontinuation, and offer them closer monitoring for proper integrated management to improve prognosis and health outcomes.