Steroid-Resistant Graves' Orbitopathy Treated with Tocilizumab in Real-World Clinical Practice: A 9-Year Single-Center Experience.

This study aimed to assess the effectiveness and safety of tocilizumab use for the treatment of active steroid-resistant Graves' orbitopathy (GO). A retrospective longitudinal study was conducted by reviewing the medical records at a single center between November 2009 and December 2018. A total of 114 patients with steroid-resistant Graves' orbitopathy were examined and treated with tocilizumab, of which 54 adults met the inclusion criteria. No concomitant medication for the treatment of orbitopathy was used. The main primary outcomes included changes from baseline in the Clinical Activity Score (CAS) and thyrotropin receptor antibody (TRAb) levels throughout therapy with tocilizumab. The absolute responses to treatment were defined as the achievement of CAS ≤ 1 and TRAb ≤ 10 U/L. A composite ophthalmic score including CAS, proptosis, eyelid retraction, and diplopia was used to evaluate individual improvement in GO. Adverse drug reactions were also assessed. Analysis of the patient's CAS and TRAb levels showed meaningful reductions during tocilizumab treatment. Differences between values at baseline and subsequent time points were statistically significant (p < 0.001 for all comparisons). The absolute CAS response (CAS = 0 or 1) was achieved in 74% (37/50) of patients after the fourth dose of tocilizumab (at week 16), with a TRAb response being achieved in 55% (23/42) of patients. The relative CAS response (reduction ≥ 2 points) was achieved in 90.9% of patients (40/44) after the first dose of tocilizumab (at week 4). Measurements of proptosis (reduction ≥ 2 mm in 78% of patients, 42/54) and eyelid retraction (reduction ≥ 2 mm in 75%, 33/44), and the prevalence of diplopia (improvement in 68%, 19/28) were significantly reduced after the last dose of tocilizumab (p < 0.001 for all comparisons). GO improved in 98% (53/54) of patients when at least two criteria of the composite evaluation were required. Four patients exhibited disease recurrence, defined as an increase in CAS of ≥2 points in the six months following the date of inactivation. Most adverse drug reactions were mild or moderate in severity. In conclusion, our data suggest that a course of at least 4 months (one monthly dose) of tocilizumab therapy provides a significant benefit to patients with active moderate-to-severe steroid-resistant GO.

Offering, participation and adherence to cardiac rehabilitation programmes in the elderly: a European comparison based on the EU-CaRE multicentre observational study.

AIMS: Cardiac rehabilitation (CR) is strongly recommended but participation of elderly patients has not been well characterized. This study aims to analyse current rates and determinants of CR referral, participation, adherence, and compliance in a contemporary European cohort of elderly patients. METHODS AND RESULTS: The EU-CaRE observational study included data from consecutive patients aged ≥ 65 with acute coronary syndrome, revascularization, stable coronary artery disease, or heart valve replacement, recruited in eight European centres. Rates and factors determining offering, participation, and adherence to CR programmes and compliance with training sessions were studied across centres, under consideration of extensive-outpatient vs. intensive-inpatient programmes. Three thousand, four hundred, and seventy-one patients were included in the offering and participation analysis. Cardiac rehabilitation was offered to 80.8% of eligible patients, formal contraindications being the main reason for not offering CR. Mean participation was 68.0%, with perceived lack of usefulness and transport issues being principal barriers. Mean adherence to CR programmes of participants in the EU-CaRE study (n = 1663) was 90.3%, with hospitalization/physical impairment as principal causes of dropout. Mean compliance with training sessions was 86.1%. Older age was related to lower offering and participation, and comorbidity was associated with lower offering, participation, adherence, and compliance. Intensive-inpatient programmes displayed higher adherence (97.1% vs. 85.9%, P < 0.001) and compliance (full compliance: 66.0% vs. 38.8%, P < 0.001) than extensive-outpatient programmes. CONCLUSION: In this European cohort of elderly patients, older age and comorbidity tackled patients' referral and uptake of CR programmes. Intensive-inpatient CR programmes showed higher completion than extensive-outpatient CR programmes, suggesting this formula could suit some elderly patients.

Combination of Tocilizumab and Steroids to Improve Mortality in Patients with Severe COVID-19 Infection: A Spanish, Multicenter, Cohort Study.

BACKGROUND: We aimed to determine the impact of tocilizumab use on severe COVID-19 (coronavirus disease 19) pneumonia mortality. METHODS: We performed a multicentre retrospective cohort study in 18 tertiary hospitals in Spain from March to April 2020. Consecutive patients admitted with severe COVID-19 treated with tocilizumab were compared to patients not treated with tocilizumab, adjusting by inverse probability of the treatment weights (IPTW). Tocilizumab's effect in patients receiving steroids during the 48 h following inclusion was analysed. RESULTS: During the study period, 506 patients with severe COVID-19 fulfilled the inclusion criteria. Among them, 268 were treated with tocilizumab and 238 patients were not. Median time to tocilizumab treatment from onset of symptoms was 11 days [interquartile range (IQR) 8-14]. Global mortality was 23.7%. Mortality was lower in patients treated with tocilizumab than in controls: 16.8% versus 31.5%, hazard ratio (HR) 0.514 [95% confidence interval (95% CI) 0.355-0.744], p < 0.001; weighted HR 0.741 (95% CI 0.619-0.887), p = 0.001. Tocilizumab treatment reduced mortality by 14.7% relative to no tocilizumab treatment [relative risk reduction (RRR) 46.7%]. We calculated a number necessary to treat of 7. Among patients treated with steroids, mortality was lower in those treated with tocilizumab than in those treated with steroids alone [10.9% versus 40.2%, HR 0.511 (95% CI 0.352-0.741), p = 0.036; weighted HR 0.6 (95% CI 0.449-0.804), p < 0.001] (interaction p = 0.094). CONCLUSIONS: These results show that survival of patients with severe COVID-19 is higher in those treated with tocilizumab than in those not treated and that tocilizumab's effect adds to that of steroids administered to non-intubated patients with COVID-19 during the first 48 h of presenting with respiratory failure despite oxygen therapy. Randomised controlled studies are needed to confirm these results. TRIAL REGISTRATION: European Union electronic Register of Post-Authorization Studies (EU PAS Register) identifier, EUPAS34415.

Bias in pharmacoepidemiologic studies using secondary health care databases: a scoping review.

BACKGROUND: The availability of clinical and therapeutic data drawn from medical records and administrative databases has entailed new opportunities for clinical and epidemiologic research. However, these databases present inherent limitations which may render them prone to new biases. We aimed to conduct a structured review of biases specific to observational clinical studies based on secondary databases, and to propose strategies for the mitigation of those biases. METHODS: Scoping review of the scientific literature published during the period 2000-2018 through an automated search of MEDLINE, EMBASE and Web of Science, supplemented with manually cross-checking of reference lists. We included opinion essays, methodological reviews, analyses or simulation studies, as well as letters to the editor or retractions, the principal objective of which was to highlight the existence of some type of bias in pharmacoepidemiologic studies using secondary databases. RESULTS: A total of 117 articles were included. An increasing trend in the number of publications concerning the potential limitations of secondary databases was observed over time and across medical research disciplines. Confounding was the most reported category of bias (63.2% of articles), followed by selection and measurement biases (47.0% and 46.2% respectively). Confounding by indication (32.5%), unmeasured/residual confounding (28.2%), outcome misclassification (28.2%) and "immortal time" bias (25.6%) were the subcategories most frequently mentioned. CONCLUSIONS: Suboptimal use of secondary databases in pharmacoepidemiologic studies has introduced biases in the studies, which may have led to erroneous conclusions. Methods to mitigate biases are available and must be considered in the design, analysis and interpretation phases of studies using these data sources.

Primary versus secondary source of data in observational studies and heterogeneity in meta-analyses of drug effects: a survey of major medical journals.

BACKGROUND: The data from individual observational studies included in meta-analyses of drug effects are collected either from ad hoc methods (i.e. "primary data") or databases that were established for non-research purposes (i.e. "secondary data"). The use of secondary sources may be prone to measurement bias and confounding due to over-the-counter and out-of-pocket drug consumption, or non-adherence to treatment. In fact, it has been noted that failing to consider the origin of the data as a potential cause of heterogeneity may change the conclusions of a meta-analysis. We aimed to assess to what extent the origin of data is explored as a source of heterogeneity in meta-analyses of observational studies. METHODS: We searched for meta-analyses of drugs effects published between 2012 and 2018 in general and internal medicine journals with an impact factor > 15. We evaluated, when reported, the type of data source (primary vs secondary) used in the individual observational studies included in each meta-analysis, and the exposure- and outcome-related variables included in sensitivity, subgroup or meta-regression analyses. RESULTS: We found 217 articles, 23 of which fulfilled our eligibility criteria. Eight meta-analyses (8/23, 34.8%) reported the source of data. Three meta-analyses (3/23, 13.0%) included the method of outcome assessment as a variable in the analysis of heterogeneity, and only one compared and discussed the results considering the different sources of data (primary vs secondary). CONCLUSIONS: In meta-analyses of drug effects published in seven high impact general medicine journals, the origin of the data, either primary or secondary, is underexplored as a source of heterogeneity.

Summarising the Evidence for Drug Safety: A Methodological Discussion of Different Meta-Analysis Approaches.

Evidence on drug safety obtained from randomised clinical trials is very limited due to, among other reasons, their relatively small sample size. Hence, combining the results of available studies can prove particularly useful. This paper reviews the different data sources for summarising drug safety outcomes, according to study design, publication of data, and origin of the information. It then discusses the various types of overviews that can be used in the study of treatment harms, focusing on meta-analyses of aggregate data and meta-analyses of individual patient data, with their advantages and drawbacks, such as publication bias and heterogeneity. Although the different approaches available for combining the results are of great utility in assessing treatment harms, none of them is free from limitations. Therefore, it might be appropriate to perform an analysis of sensitivity to assess whether the results are sensitive to the technique that has been used.

Efficacy of pancreatic enzyme replacement therapy in chronic pancreatitis: systematic review and meta-analysis.

OBJECTIVE: The benefits of pancreatic enzyme replacement therapy (PERT) in chronic pancreatitis (CP) are inadequately defined. We have undertaken a systematic review and meta-analysis of randomised controlled trials of PERT to determine the efficacy of PERT in exocrine pancreatic insufficiency (EPI) from CP. DESIGN: Major databases were searched from 1966 to 2015 inclusive. The primary outcome was coefficient of fat absorption (CFA). Effects of PERT versus baseline and versus placebo, and of different doses, formulations and schedules were determined. RESULTS: A total of 17 studies (511 patients with CP) were included and assessed qualitatively (Jadad score). Quantitative data were synthesised from 14 studies. PERT improved CFA compared with baseline (83.7±6.0 vs 63.1±15.0, p<0.00001; I2=89%) and placebo (83.2±5.5 vs 67.4±7.0, p=0.0001; I2=86%). PERT improved coefficient of nitrogen absorption, reduced faecal fat excretion, faecal nitrogen excretion, faecal weight and abdominal pain, without significant adverse events. Follow-up studies demonstrated that PERT increased serum nutritional parameters, improved GI symptoms and quality of life without significant adverse events. High-dose or enteric-coated enzymes showed a trend to greater effectiveness than low-dose or non-coated comparisons, respectively. Subgroup, sensitive and meta-regression analyses revealed that sample size, CP diagnostic criteria, study design and enzyme dose contributed to heterogeneity; data on health inequalities were lacking. CONCLUSIONS: PERT is indicated to correct EPI and malnutrition in CP and may be improved by higher doses, enteric coating, administration during food and acid suppression. Further studies are required to determine optimal regimens, the impact of health inequalities and long-term effects on nutrition.

Diverging Conclusions from the Same Meta-Analysis in Drug Safety: Source of Data (Primary Versus Secondary) Takes a Toll.

INTRODUCTION: Meta-analyses of observational studies represent an important tool for assessing efficacy and safety in the pharmacoepidemiologic field. The data from the individual studies are either primary (i.e., collected through interviews or self-administered questionnaires) or secondary (i.e., collected from databases that were established for other purposes). So far, the origin of the data (primary vs. secondary) has not been systematically assessed as a source of heterogeneity in pharmacoepidemiologic meta-analyses. OBJECTIVE: The aim was to assess the impact of considering the source of exposure data as a criterion in sensitivity and subgroup analysis on the conclusions of drug safety meta-analyses. METHODS: We selected meta-analyses published between 2013 and 2015 in which the intake of frequently used over-the-counter medicines was either the main exposure or a concomitant treatment and the outcome had short latency and induction periods. We stratified the results by origin of data (primary vs. secondary) and compared the new results to those presented originally in the meta-analyses. RESULTS: We used four meta-analyses that fulfilled our criteria of inclusion. The results were selective serotonin reuptake inhibitors and upper gastrointestinal bleeding: original estimate odds ratio (OR) = 1.71 [95% confidence interval (CI) 1.44-2.04], OR primary data = 1.19 (95% CI 0.90-1.58), OR secondary data = 1.81 (95% CI 1.50-2.17); proton pump inhibitors and cardiac events: original estimate hazard ratio (HR) = 1.35 (95% CI 1.18-1.54), HR primary data = 1.05 (95% CI 0.87-1.26), HR secondary data = 1.43 (95% CI 1.23-1.66); non-aspirin non-steroidal anti-inflammatory drugs and myocardial infarction: original estimate risk ratio (RR) = 1.08 (95% CI 0.95-1.22), RR primary data = 0.57 (95% CI 0.34-0.96), RR secondary data = 1.15 (95% CI 1.03-1.28); paracetamol during pregnancy and childhood asthma: original estimate OR = 1.32 (95% CI 1.14-1.52), OR primary data = 1.23 (95% CI 1.06-1.42), OR secondary data = 1.53 (95% CI 1.33-1.75). CONCLUSIONS: The results after stratification are considerably modified. It is crucial to explore the origin of the data, either primary or secondary, as a source of heterogeneity in pharmacoepidemiologic meta-analyses to avoid misleading conclusions.

¿Son equivalentes los genéricos y las marcas en el tratamiento de la enfermedad de Alzheimer? / Are generics and brand name medicines equivalent in Alzheimer’s disease treatment?

Los genéricos son a veces objeto de dudas y malentendidos por parte del médico o del paciente. En el caso del paciente con enfermedad de Alzheimer, el «baile» de genéricos puede ser un motivo de preocupación y causar problemas en la identificación del tratamiento habitual. Sin embargo, la eficacia y la seguridad del medicamento genérico están perfectamente avaladas al haberse demostrado su bioequivalencia con el medicamento innovador o de referencia. La bioequivalencia tiene como base una metodología cuyo fundamento es garantizar no solo que el medicamento genérico tiene la misma cantidad de principio activo que el medicamento de referencia, sino también que se absorbe exactamente del mismo modo, lo que permite asumir que producirá los mismos efectos sistémicos. El menor precio del genérico está sujeto a diversos factores, pero no se debe a diferencias en calidad, ya que su fabricación cumple con idénticos estándares a los del medicamento de referencia. Algunos conceptos relevantes en este campo son los de «prescribilidad », intercambiabilidad y políticas de sustitución. Así, un medicamento genérico autorizado puede ser prescrito con las mismas garantías de calidad, eficacia y seguridad que el medicamento de referencia y se debe considerar intercambiable, si bien es preferible evitar sustituciones innecesarias en los pacientes (AU)

The use of generic drugs is often surrounded by misunderstandings and questions, from patients and physicians. The switch between generic drugs is frequently a concern because it can difficult the ability of Alzheimer’s patients to recognize their daily medication. The efficacy and safety of a generic drug is fully endorsed by demonstrating its bioequivalence with the reference drug. The demonstration of bioequivalence guarantees not only that the generic drug contains the same active substance quantity, but it is also absorbed in the same manner than the reference drug. This methodology allows us to conclude that both drugs produce the same systemic effects. The lower price of a generic drug is due to several different factors, but none of them incur in differences in quality, since the manufacture of a generic drug follows identical requirements to those followed by the reference drug. "Prescribility", "interchangeability" and "drug substitution" policies are relevant concepts to discuss in the context of generic drugs use. In that sense, an approved generic drug can be prescribed with the same quality, efficacy and safety guaranties that those of the reference drug and both of them can be considered exchangeable. However, it is preferred to avoid any unnecessary drug substitutions in a patient chronic treatment (AU)