Las fuentes de datos en farmacoepidemiología como generadoras de sesgos y heterogeneidad en metanálisis

En este trabajo se revisa la literatura científica de las dos últimas décadas cuyo propósito fuese poner de manifiesto la existencia de algún tipo de sesgo en estudios clínicos observacionales con fuentes de datos secundarias, y se proponen estrategias para la mitigación de dichos sesgos. A continuación se discuten metodológicamente las diferentes técnicas de metanálisis disponibles para resumir la evidencia sobre seguridad de medicamentos, y se ilustra, mediante varios ejemplos, cómo difieren las conclusiones a partir de un mismo metanálisis cuando se considera el tipo de fuente de datos, primaria o secundaria, como una variable en el análisis de heterogeneidad. Por último, se evalúa el grado en que el origen de los datos se explora como una fuente de heterogeneidad en metanálisis de estudios observacionales publicados en las principales revistas médicas

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

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

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.publishe

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

We aimed to determine the impact of tocilizumab use on severe COVID-19 (coronavirus disease 19) pneumonia mortality. 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. 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). 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. European Union electronic Register of Post-Authorization Studies (EU PAS Register) identifier, EUPAS34415 The online version of this article (10.1007/s40121-020-00373-8) contains supplementary material, which is available to authorized users

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

Abstract 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

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 &lt; 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 &lt; 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

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

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 /= 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 /=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