Association between diabetes overtreatment in older multimorbid patients and clinical outcomes: an ancillary European multicentre study.

BACKGROUND Diabetes overtreatment is a frequent and severe issue in multimorbid older patients with type 2 diabetes (T2D). OBJECTIVE This study aimed at assessing the association between diabetes overtreatment and 1-year functional decline, hospitalisation and mortality in older inpatients with multimorbidity and polypharmacy. METHODS Ancillary study of the European multicentre OPERAM project on multimorbid patients aged ≥70 years with T2D and glucose-lowering treatment (GLT). Diabetes overtreatment was defined according to the 2019 Endocrine Society guideline using HbA1c target range individualised according to the patient's overall health status and the use of GLT with a high risk of hypoglycaemia. Multivariable regressions were used to assess the association between diabetes overtreatment and the three outcomes. RESULTS Among the 490 patients with T2D on GLT (median age: 78 years; 38% female), 168 (34.3%) had diabetes overtreatment. In patients with diabetes overtreatment as compared with those not overtreated, there was no difference in functional decline (29.3% vs 38.0%, P = 0.088) nor hospitalisation rates (107.3 vs 125.8/100 p-y, P = 0.115) but there was a higher mortality rate (32.8 vs 21.4/100 p-y, P = 0.033). In multivariable analyses, diabetes overtreatment was not associated with functional decline nor hospitalisation (hazard ratio, HR [95%CI]: 0.80 [0.63; 1.02]) but was associated with a higher mortality rate (HR [95%CI]: 1.64 [1.06; 2.52]). CONCLUSIONS Diabetes overtreatment was associated with a higher mortality rate but not with hospitalisation or functional decline. Interventional studies should be undertaken to test the effect of de-intensifying GLT on clinical outcomes in overtreated patients

Healthcare Costs and Health-Related Quality of Life in Older Multimorbid Patients After Hospitalization.

OBJECTIVES We identified factors associated with healthcare costs and health-related quality of life (HRQoL) of multimorbid older adults with polypharmacy. METHODS Using data from the OPERAM (OPtimising thERapy to prevent Avoidable hospital admissions in the Multimorbid older people) trial, we described the magnitude and composition of healthcare costs, and time trends of HRQoL, during 1-year after an acute-care hospitalization. We performed a cluster analysis to identify groups with different cost and HRQoL trends. Using multilevel models, we also identified factors associated with costs and HRQoL. RESULTS Two months after hospitalization monthly mean costs peaked (CHF 7'124) and HRQoL was highest (0.67). They both decreased thereafter. Age, falls, and comorbidities were associated with higher 1-year costs. Being female and housebound were negatively associated with HRQoL, while moderate alcohol consumption had a positive association. Being independent in daily activities was associated with lower costs and higher HRQoL. CONCLUSION Although only some identified potential influences on costs and HRQoL are modifiable, our observations support the importance of prevention before health deterioration in older people with multimorbid illness and associated polypharmacy

Benzodiazepine Receptor Agonists Use and Cessation Among Multimorbid Older Adults with Polypharmacy: Secondary Analysis from the OPERAM Trial.

BACKGROUND Benzodiazepine receptor agonists (BZRAs) are commonly prescribed in older adults despite an unfavorable risk-benefit ratio. Hospitalizations may provide a unique opportunity to initiate BZRA cessation, yet little is known about cessation during and after hospitalization. We aimed to measure the prevalence of BZRA use before hospitalization and the rate of cessation 6 months later, and to identify factors associated with these outcomes. METHODS We conducted a secondary analysis of a cluster randomized controlled trial (OPtimising thERapy to prevent Avoidable hospital admissions in the Multimorbid elderly [OPERAM]), comparing usual care and in-hospital pharmacotherapy optimization in adults aged 70 years or over with multimorbidity and polypharmacy in four European countries. BZRA cessation was defined as taking one or more BZRA before hospitalization and not taking any BZRA at the 6-month follow-up. Multivariable logistic regression was performed to identify factors associated with BZRA use before hospitalization and with cessation at 6 months. RESULTS Among 1601 participants with complete 6-month follow-up data, 378 (23.6%) were BZRA users before hospitalization. Female sex (odds ratio [OR] 1.52 [95% confidence interval 1.18-1.96]), a higher reported level of depression/anxiety (OR up to 2.45 [1.54-3.89]), a higher number of daily drugs (OR 1.08 [1.05-1.12]), use of an antidepressant (OR 1.74 [1.31-2.31]) or an antiepileptic (OR 1.46 [1.02-2.07]), and trial site were associated with BZRA use. Diabetes mellitus (OR 0.60 [0.44-0.80]) was associated with a lower probability of BZRA use. BZRA cessation occurred in 86 BZRA users (22.8%). Antidepressant use (OR 1.74 [1.06-2.86]) and a history of falling in the previous 12 months (OR 1.75 [1.10-2.78]) were associated with higher BZRA cessation, and chronic obstructive pulmonary disease (COPD) (OR 0.45 [0.20-0.91]) with lower BZRA cessation. CONCLUSION BZRA prevalence was high among included multimorbid older adults, and BZRA cessation occurred in almost a quarter of them within 6 months after hospitalization. Targeted BZRA deprescribing programs could further enhance cessation. Specific attention is needed for females, central nervous system-acting co-medication, and COPD co-morbidity. REGISTRATION ClinicalTrials.gov identifier: NCT02986425. December 8, 2016

Benzodiazepine Receptor Agonists Use and Cessation Among Multimorbid Older Adults with Polypharmacy: Secondary Analysis from the OPERAM Trial

BACKGROUND Benzodiazepine receptor agonists (BZRAs) are commonly prescribed in older adults despite an unfavorable risk-benefit ratio. Hospitalizations may provide a unique opportunity to initiate BZRA cessation, yet little is known about cessation during and after hospitalization. We aimed to measure the prevalence of BZRA use before hospitalization and the rate of cessation 6 months later, and to identify factors associated with these outcomes. METHODS We conducted a secondary analysis of a cluster randomized controlled trial (OPtimising thERapy to prevent Avoidable hospital admissions in the Multimorbid elderly [OPERAM]), comparing usual care and in-hospital pharmacotherapy optimization in adults aged 70 years or over with multimorbidity and polypharmacy in four European countries. BZRA cessation was defined as taking one or more BZRA before hospitalization and not taking any BZRA at the 6-month follow-up. Multivariable logistic regression was performed to identify factors associated with BZRA use before hospitalization and with cessation at 6 months. RESULTS Among 1601 participants with complete 6-month follow-up data, 378 (23.6%) were BZRA users before hospitalization. Female sex (odds ratio [OR] 1.52 [95% confidence interval 1.18-1.96]), a higher reported level of depression/anxiety (OR up to 2.45 [1.54-3.89]), a higher number of daily drugs (OR 1.08 [1.05-1.12]), use of an antidepressant (OR 1.74 [1.31-2.31]) or an antiepileptic (OR 1.46 [1.02-2.07]), and trial site were associated with BZRA use. Diabetes mellitus (OR 0.60 [0.44-0.80]) was associated with a lower probability of BZRA use. BZRA cessation occurred in 86 BZRA users (22.8%). Antidepressant use (OR 1.74 [1.06-2.86]) and a history of falling in the previous 12 months (OR 1.75 [1.10-2.78]) were associated with higher BZRA cessation, and chronic obstructive pulmonary disease (COPD) (OR 0.45 [0.20-0.91]) with lower BZRA cessation. CONCLUSION BZRA prevalence was high among included multimorbid older adults, and BZRA cessation occurred in almost a quarter of them within 6 months after hospitalization. Targeted BZRA deprescribing programs could further enhance cessation. Specific attention is needed for females, central nervous system-acting co-medication, and COPD co-morbidity. REGISTRATION ClinicalTrials.gov identifier: NCT02986425. December 8, 2016

Collaborative approach to Optimise MEdication use for Older people in Nursing homes (COME-ON): study protocol of a cluster controlled trial

BACKGROUND: Ageing has become a worldwide reality and presents new challenges for the health-care system. Research has shown that potentially inappropriate prescribing, both potentially inappropriate medications and potentially prescribing omissions, is highly prevalent in older people, especially in the nursing home setting. The presence of potentially inappropriate medications/potentially prescribing omissions is associated with adverse drug events, hospitalisations, mortality and health-care costs. The Collaborative approach to Optimise MEdication use for Older people in Nursing homes (COME-ON) study aims to evaluate the effect of a complex, multifaceted intervention, including interdisciplinary case conferences, on the appropriateness of prescribing of medicines for older people in Belgian nursing homes. METHODS/DESIGN: A multicentre cluster-controlled trial is set up in 63 Belgian nursing homes (30 intervention; 33 control). In each of these nursing homes, 35 residents (≥65 years) are selected for participation. The complex, multifaceted intervention comprises (i) health-care professional education and training, (ii) local concertation (discussion on the appropriate use of at least one medication class at the level of the nursing home) and (iii) repeated interdisciplinary case conferences between general practitioner, nurse and pharmacist to perform medication review for each included nursing home resident. The control group works as usual. The study period lasts 15 months. The primary outcome measures relate to the appropriateness of prescribing and are defined as (1) among residents who had at least one potentially inappropriate medication/potentially prescribing omission at baseline, the proportion of them for whom there is a decrease of at least one of these potentially inappropriate medications/potentially prescribing omissions at the end of study, and (2) among all residents, the proportion of them for whom at least one new potentially inappropriate medication/potentially prescribing omission is present at the end of the study, compared to baseline. The secondary outcome measures include individual components of appropriateness of prescribing, medication use, outcomes of the case conferences, clinical outcomes and costs. A process evaluation (focusing on implementation, causal mechanisms and contextual factors) will be conducted alongside the study. DISCUSSION: The COME-ON study will contribute to a growing body of knowledge concerning the effect of complex interventions on the use of medicines in the nursing home setting, and on factors influencing their effect. The results will inform policymakers on strategies to implement in the near future. TRIAL REGISTRATION: Current Controlled Trials ISRCTN66138978

Cost-effectiveness of a structured medication review approach for multimorbid older adults: Within-trial analysis of the OPERAM study

BACKGROUND Inappropriate polypharmacy has been linked with adverse outcomes in older, multimorbid adults. OPERAM is a European cluster-randomized trial aimed at testing the effect of a structured pharmacotherapy optimization intervention on preventable drug-related hospital admissions in multimorbid adults with polypharmacy aged 70 years or older. Clinical results of the trial showed a pattern of reduced drug-related hospital admissions, but without statistical significance. In this study we assessed the cost-effectiveness of the pharmacotherapy optimisation intervention. METHODS We performed a pre-planned within-trial cost-effectiveness analysis (CEA) of the OPERAM intervention, from a healthcare system perspective. All data were collected within the trial apart from unit costs. QALYs were computed by applying the crosswalk German valuation algorithm to EQ-5D-5L-based quality of life data. Considering the clustered structure of the data and between-country heterogeneity, we applied Generalized Structural Equation Models (GSEMs) on a multiple imputed sample to estimate costs and QALYs. We also performed analyses by country and subgroup analyses by patient and morbidity characteristics. RESULTS Trial-wide, the intervention was numerically dominant, with a potential cost-saving of CHF 3'588 (95% confidence interval (CI): -7'716; 540) and gain of 0.025 QALYs (CI: -0.002; 0.052) per patient. Robustness analyses confirmed the validity of the GSEM model. Subgroup analyses suggested stronger effects in people at higher risk. CONCLUSION We observed a pattern towards dominance, potentially resulting from an accumulation of multiple small positive intervention effects. Our methodological approaches may inform other CEAs of multi-country, cluster-randomized trials facing presence of missing values and heterogeneity between centres/countries

Comparison of 6 Mortality Risk Scores for Prediction of 1-Year Mortality Risk in Older Adults With Multimorbidity.

Importance The most appropriate therapy for older adults with multimorbidity may depend on life expectancy (ie, mortality risk), and several scores have been developed to predict 1-year mortality risk. However, often, these mortality risk scores have not been externally validated in large sample sizes, and a head-to-head comparison in a prospective contemporary cohort is lacking. Objective To prospectively compare the performance of 6 scores in predicting the 1-year mortality risk in hospitalized older adults with multimorbidity. Design, Setting, and Participants This prognostic study analyzed data of participants in the OPERAM (Optimising Therapy to Prevent Avoidable Hospital Admissions in Multimorbid Older People) trial, which was conducted between December 1, 2016, and October 31, 2018, in surgical and nonsurgical departments of 4 university-based hospitals in Louvain, Belgium; Utrecht, the Netherlands; Cork, Republic of Ireland; and Bern, Switzerland. Eligible participants in the OPERAM trial had multimorbidity (≥3 coexisting chronic diseases), were aged 70 years or older, had polypharmacy (≥5 long-term medications), and were admitted to a participating ward. Data were analyzed from April 1 to September 30, 2020. Main Outcomes and Measures The outcome of interest was any-cause death occurring in the first year of inclusion in the OPERAM trial. Overall performance, discrimination, and calibration of the following 6 scores were assessed: Burden of Illness Score for Elderly Persons, CARING (Cancer, Admissions ≥2, Residence in a nursing home, Intensive care unit admit with multiorgan failure, ≥2 Noncancer hospice guidelines) Criteria, Charlson Comorbidity Index, Gagné Index, Levine Index, and Walter Index. These scores were assessed using the following measures: Brier score (0 indicates perfect overall performance and 0.25 indicates a noninformative model); C-statistic and 95% CI; Hosmer-Lemeshow goodness-of-fit test and calibration plots; and sensitivity, specificity, and positive and negative predictive values. Results The 1879 patients in the study had a median (IQR) age of 79 (74-84) years and 835 were women (44.4%). The median (IQR) number of chronic diseases was 11 (8-16). Within 1 year, 375 participants (20.0%) died. Brier scores ranged from 0.16 (Gagné Index) to 0.24 (Burden of Illness Score for Elderly Persons). C-statistic values ranged from 0.62 (95% CI, 0.59-0.65) for Charlson Comorbidity Index to 0.69 (95% CI, 0.66-0.72) for the Walter Index. Calibration was good for the Gagné Index and moderate for other mortality risk scores. Conclusions and Relevance Results of this prognostic study suggest that all 6 of the 1-year mortality risk scores examined had moderate prognostic performance, discriminatory power, and calibration in a large cohort of hospitalized older adults with multimorbidity. Overall, none of these mortality risk scores outperformed the others, and thus none could be recommended for use in daily clinical practice

Impact of a rare disease on Public Health today and tomorrow : the case of haemophilia

The aim of this thesis was to study some implications of a rare disease on Public Health in Belgium, taking the example of haemophilia, a rare but well-known haemorrhagic X-linked disease. If untreated, the bleeding tendency in patients with haemophiliac may induce spontaneous bleeding episodes leading to serious complications, including premature death. However, substitutive treatments that consist of intravenous infusions of factor VIII or factor IX clotting concentrates which can be administered in a preventive or curative way are presently available. The first section of this thesis addresses the optimal substitutive treatment of haemophilia, which allows the treatment or the prevention of haemorrhagic complications. In this context, a correct dosing of exogenous coagulation factor VIII is crucial as under-dosing puts patients at risk of haemorrhage, and over-dosing results in a waste of expensive concentrates. We estimated the correct dosing of factor VIII concentrates in patients with haemophilia A in relation to morphometric variables. The second section of this thesis evaluated some current limitations of developing new treatments for haemophilia. Developments of new treatments are indeed only possible through clinical studies requiring the active collaboration of patients. We assessed factors influencing the motivation of patients to participate in clinical studies. Finally, we integrated this work in a general public health perspective by investigating the burden and cost of haemophilia. The consumption of coagulation factors needed to treat haemophilia and its associated cost is steadily increasing in Belgium and other developed countries. Since no global cost estimation of haemophilia is available in our country, we estimated for the first time the total financial burden of haemophilia in Belgium. In addition to cost calculations, we quantified the disease burden related to haemophilia in Belgium, considering the physical and psychological impacts of this rare disease, through Disability-Adjusted Life Year (DALY) calculations.(SP - Sciences de la santé publique) -- UCL, 201

Maladies rares et médicaments orphelins en Belgique et dans l’Union Européenne : où en est-on ?

Les maladies rares, qui touchent moins de 5 personnes sur 10000, sont devenues une priorité de santé publique en Belgique et dans l’Union Européenne (UE). Fin 1999, le Parlement Européen et le Conseil de l’UE publiaient le règlement (CE) N° 141/2000 concernant les médicaments orphelins, médicaments destinés à diagnostiquer, prévenir, ou traiter les maladies rares. Il permet aux firmes pharmaceutiques de pouvoir bénéficier de certains incitants de la part de l’UE pour développer ces médicaments orphelins qui ne seraient pas ou peu rentables étant donné le faible nombre de patients. Depuis 2000, 1586 demandes du statut de médicament orphelin ont été introduites, dont 98.5% ont été accordées. Sur les 1563 demandes octroyées, plus d’un tiers concerne une tumeur rare (37.4%, n=584/1563) et un quart une maladie rare endocrinienne, nutritionnelle ou métabolique (16.1%, n=251/1563). Au total, 96 médicaments orphelins différents ont obtenu une autorisation de mise sur le marché depuis 2000, dont la moitié entre 2011 et octobre 2015, démontrant le boom du développement des médicaments orphelins. Toutefois, le coût élevé de ces médicaments pose de nouveaux défis pour la durabilité de notre système de santé. En avril 2015, M. de Block, Ministre belge des Affaires Sociales et de la Santé Publique, a annoncé, avec son homologue des Pays-Bas, le projet commun de négocier ensemble, entre autres, le prix des médicaments orphelins avec les firmes pharmaceutiques. Ce projet pilote, qui débutera en 2016, démontre l’importance d’une collaboration active entre les différents pays de l’UE concernant les maladies rares et les médicaments orphelins[Rare diseases and orphan drugs in Belgium and in the european Union: what is the current situation?] Rare diseases, which affect less than 5 persons in 10,000, have become a public health priority in Belgium and the European Union (EU). Towards the end of 1999, the European Parliament and Council of EU published the regulation (EC) No 141/2000 on orphan medicinal products that are intended for the diagnosis, prevention, or treatment of rare diseases. This regulation allows pharmaceutical companies to benefit from different incentives from the EU to develop these orphan drugs, which are considered as having little or no profitability for manufacturers, given the low number of patients concerned. Since 2000, 1,586 applications to receive the orphan designation have been submitted, of which 98.5% were granted. Among the 1,563 granted designations, more than one-third were granted for rare tumors (37.4%, n=584/1563), and one-quarter for rare endocrine, nutritional, or metabolic diseases (16.1%, n=251/1563). All in all, 96 different orphan drugs have received a marketing authorisation since 2000, half of them between 2011 and October 2015, illustrating the boom in the development of orphan medicinal products. However, the high costs associated with these products pose new challenges for our health system’s sustainability. In April 2015, M. de Block, the Belgian Minister of Social Affairs and Public Health, announced collaborating with her Dutch counterpart in order to negotiate fair pricing of orphan medicinal products with the pharmaceutical companies. This pilot project, likely to start in 2016, reveals the relevance of EU countries’ active collaboration in the field of rare diseases and orphan drugs

Impact of being overweight on factor VIII dosing in children with haemophilia A.

Introduction. Treatment of haemophilia A (HA) requires infusions of factor VIII (FVIII) concentrates. The number of FVIII units infused to obtain a specific circulating FVIII level is calculated with the formula: [body weight (BW) (kg) × desired FVIII increase (%)]/2, with the assumption that each unit of FVIII infused per kg of BW increases the circulating FVIII level by 2%. Aim. The aim of this study was to evaluate the impact of several morphometric parameters (BW, body mass index (BMI)-for-age, height), age and type of FVIII concentrate on FVIII recovery in children with HA. Methods. A total of 66 children aged between 10 and 18 with severe HA selected from six pharmacokinetic (PK) clinical trials using two recombinant FVIII concentrates were included in the analysis. Regression tree (RT) was used to identify predictors of FVIII recovery. Results. The median age was 14.5 years with a median FVIII recovery of 2.09 for all children. The median FVIII recovery was not significantly different between age groups. Two groups were created by RT: children with a BMI-for-age percentile <P95 (Median FVIII recovery: 1.94) and obese children with a BMI-for-age percentile ≥P95 (Median FVIII recovery: 2.65). The FVIII recovery was significantly different between these two groups (P < 0.001). Conclusion. These results are consistent with previous studies conducted in adults with HA and confirm that the long-held and current practice of applying an arbitrary and universal recovery of two to the calculations of FVIII dosage should be abolished in both children and adults