Are all JAK inhibitors for the treatment of rheumatoid arthritis equivalent? An adjusted indirect comparison of the efficacy of tofacitinib, baricitinib, upadacitinib, and filgotinib.

INTRODUCTION: Comparisons of Janus kinase inhibitors (JAKi) for treatment of rheumatoid arthritis in patients with inadequate response to biologic disease-modifying anti-rheumatic drugs are lacking. We assessed the relative efficacy and safety of four JAKi (tofacitinib, baricitinib, upadacitinib, and filgotinib) in this context. METHOD: We performed an adjusted indirect comparison (IC) of randomized clinical trials using Bucher's method with an IC and mixed calculator. Endpoints were Disease Activity Score C-reactive protein (DAS28-CRP) and American College of Rheumatology-20 (ACR20). Equivalence was assessed using the equivalent therapeutic alternatives (ETA) guidelines. RESULTS: We included four of 133 potentially relevant studies. IC showed no statistically significant differences between the four JAKi regarding DAS28-CRP < 3.2. Results were similar in terms of ACR20 except for tofacitinib showing lower efficacy than upadacitinib (RAR -18.4% [IC95% -33.4 to -3.5], p=0.0157). Statistically significant differences were related to the relevant difference for tofacitinib in both endpoints. Despite no statistical differences for baricitinib, we observed a probably clinically relevant difference regarding DAS28-CRP. Probably clinically relevant differences were found for tofacitinib vs. upadacitinib in both endpoints, and for baricitinib vs. upadacitinib in DAS28-CRP. Safety, drug-drug interactions, and convenience considerations did not modify the result of therapeutic equivalence assessment based on efficacy data. CONCLUSIONS: In conclusion, our results show that filgotinib and upadacitinib are ETA. Baricitinib and upadacitinib are also ETA due to a lack of clear differences and for showing superiority over placebo. The results for tofacitinib and upadacitinib show some inconsistency and more data are needed. Key Points • To date, neither a head-to-head comparison nor an indirect comparison between the Janus kinase inhibitors has been performed in patients with rheumatoid arthritis and an inadequate response to biologic disease-modifying anti-rheumatic drugs. • We performed an adjusted indirect comparison that included randomized clinical trials of tofacitinib, baricitinib, upadacitinib, and filgotinib to assess their equivalence in this scenario. • Our results show that baricitinib and filgotinib are equivalent therapeutic alternatives compared to upadacitinib. However, there is some inconsistency in the results of tofacitinib in front of upadacitinib.

[Translated article] Usefulness of ICD-10 diagnostic triggers to identify adverse drug events in emergency care.

OBJECTIVES: To assess the usefulness of a tool based on ICD-10 diagnostic codes to identify patients who consult an emergency department for adverse drug events (ADE). METHODS: Prospective observational study, in which patients discharged from an emergency department during May to August 2022 with a diagnosis coded with one of the 27 ICD-10 diagnoses considered as triggers were included. ADE confirmation was carried out by analyzing drugs prescribed prior to admission, and through a discussion among experts and a phone interview with patients after hospital discharge. RESULTS: 1143 patients with trigger diagnoses were evaluated, of which 310 (27.1%) corresponded to patients whose emergency visit was attributed to an ADE. A 58.4% of ADE consultations were found with three diagnostic codes: K59.0-Constipation (n = 87; 28.1%), I16.9-Hypertensive Crisis (n = 72; 23.2%) and I95.1-Orthostatic hypotension (n = 22; 7.1%). The diagnoses with the highest degree of association with consultations attributed to ADE were E16.2-Hypoglycemia, unspecified (73.7%) and E11.65-Type 2 diabetes mellitus with hyperglycemia (71.4%), while diagnoses D62-Acute posthemorrhagic anemia and I74.3-Embolism and thrombosis of arteries of the lower limbs were not attributed to any case of ADE. CONCLUSIONS: The ICD-10 codes associated with trigger diagnoses are a useful tool to identify patients who consult the emergency services with ADE and could be used to apply secondary prevention programs to avoid new consultations to the health care system.

Usefulness of ICD-10 diagnosis triggers to identify adverse drug events in emergency care. / Utilidad de los diagnósticos alertantes CIE-10 para identificar acontecimientos adversos por los medicamentos en los servicios de urgencias.

OBJECTIVES: To assess the usefulness of a tool based on ICD-10 diagnostic codes to identify patients who consult an emergency department for adverse drug events (ADE). METHODS: Prospective observational study, in which patients discharged from an emergency department during May to August 2022 with a diagnosis coded with one of the 27 ICD-10 diagnoses considered as triggers were included. ADE confirmation was carried out by analyzing drugs prescribed prior to admission, and through a discussion among experts and a phone interview with patients after hospital discharge. RESULTS: 1,143 patients with trigger diagnoses were evaluated, of which 310 (27.1%) corresponded to patients whose emergency visit was attributed to an ADE. A 58.4% of ADE consultations were found with three diagnostic codes: K59.0-Constipation (n = 87; 28.1%), I16.9-Hypertensive Crisis (n = 72; 23.2%) and I95.1-Orthostatic hypotension (n = 22; 7.1%). The diagnoses with the highest degree of association with consultations attributed to ADE were E16.2-Hypoglycemia, unspecified (73.7%) and E11.65-Type 2 diabetes mellitus with hyperglycemia (71.4%), while diagnoses D62-Acute posthemorrhagic anemia and I74.3-Embolism and thrombosis of arteries of the lower limbs were not attributed to any case of ADE. CONCLUSIONS: The ICD-10 codes associated with trigger diagnoses are a useful tool to identify patients who consult the emergency services with ADE and could be used to apply secondary prevention programs to avoid new consultations to the health care system.

Anticholinergic burden and revisit risk in frail patients with pharmacological sleepiness.

OBJECTIVE: Drug-induced sleepiness is a frequent cause of emergency department (ED) visits for frail patients. The aim of this study was to assess the impact of anticholinergic burden on 90-day revisitation risk for frail patients who visit the ED due to drug-induced sleepiness. METHODS: This was a retrospective study in which patients treated at a fragility care area of an ED who sought consultation for drug-associated sleepiness from June 2020 to June 2021 were included. To evaluate the 90-day revisitation risk factors, a multivariate analysis was performed, including those factors with a p<0.200 from a previous univariate model. A Cox regression model was performed to assess the impact of a high burden on the time until 90-day ED revisitation. RESULTS: One hundred and forty-eight patients were included (mean age 80.7±12.3 years). The median number of drugs that patients were currently on at emergency admission was eight (range 2-19), while at hospital discharge it was nine (range 2-20), with the median number of central nervous system (CNS) depressant drugs on admission being three (range 1-6). Thirty-five (23.6%) patients revisited the ED 90 days after discharge for sleepiness or agitation. In the multivariate model, a significant association was observed between a high anticholinergic burden during treatment at discharge (OR 3.74, 95% CI 1.36 to 9.71), chronic kidney disease (OR 2.87, 95% CI 1.19 to 6.81), and the risk of 90-day revisitation. Patients with high anticholinergic burden had a shorter time to revisit than those with medium or low anticholinergic burden (HR 1.96, 95% CI 1.05 to 3.99). CONCLUSIONS: Patients with pharmacological sleepiness and a high anticholinergic burden in their chronic treatment carry a greater risk of revisitation to EDs, and should be considered candidates for specific interventions after visiting these units.

Cost-effectiveness analysis of implementing a secondary prevention programme in those patients who visited an emergency department for drug-related problems.

OBJECTIVE: To evaluate the cost-effectiveness of a secondary prevention programme in patients admitted to the emergency department due to drug-related problems (DRPs). METHODS: A decision model compared costs and outcomes of patients with DRPs admitted to the emergency department. Model variables and costs, along with their distributions, were obtained from the trial results and literature. The study was performed from the perspective of the National Health System including only direct costs. KEY FINDINGS: The implementation of a secondary prevention programme for DRPs reduces costs associated with emergency department revisits, with an annual net benefit of €87 639. Considering a mortality rate attributable to readmission of 4.7%, the cost per life-years gained (LYG) with the implementation of this programme was €2205. In the short term, the reduction in the number of revisits following the programme implementation was the variable that most affected the model, with the benefit threshold value corresponding to a relative reduction of 12.4% of the number of revisits of patients with DRPs to obtain benefits. CONCLUSIONS: Implementing a secondary prevention programme is cost-effective for patients with DRPs admitted to the emergency department. Implementation costs will be exceeded by reducing revisits to the emergency department.

Cefepime Dosing Requirements in Elderly Patients Attended in the Emergency Rooms.

OBJECTIVE: This study aimed to assess the probability of reaching an adequate pharmacokinetic/pharmacodynamic (pK/pD) index for different cefepime dosages in frail patients with bacteremia treated in the emergency room. METHODS: Simulation study based on Gram-negative bacterial strains that cause bacteremia. The probability of reaching a time above the minimum inhibitory concentration (MIC) at 50% and 100% dosing intervals (fT > 50 and fT > 80% MIC) was assessed for two different renal clearance intervals. RESULTS: One hundred twenty nine strains were collected, the predominant species being Escherichia coli (n = 83 [64.3%]). In patients with a ClCr of 30 mL/min, an fT > 50% MIC was reached in more than 90% of the simulations. However, a dose of at least 1 g every 12 h must be administered to reach an fT > 80% MIC. In patients with a ClCr of 30-60 mL/min, the probability of reaching an fT > 50% MIC was higher than 90% with doses of 1 g every 8 h or more, but this value was not reached in > 90% simulations for any of the doses tested in this study. CONCLUSIONS: Standard cefepime dosing can reach an adequate PK/PD index in frail patients. Nevertheless, a high dose or extended infusion is necessary to reach an fT > 80% MIC in patients with a ClCr > 60 mL/min.

Development of an Emergency Revisit Score for Patients With Drug-Related Problems.

Background: Drug-related problems (DRPs) are a frequent reason for emergency departments (EDs) visits. However, data about the risk factors associated with EDs revisits are limited. Objective: To develop and validate a predictive model indicating the risk factors associated with EDs revisit within 30 days of the first visit. Methods: A retrospective cohort study was conducted involving patients who attended an ED for DRPs related to cardiovascular drugs. A 30-day prediction model was created in a derivation cohort by logistic regression. An integer score proportional to the regression coefficient was assigned to the variables with P < .100 in the multivariate analysis. Results: 581 patients (mean age: 80.0 [12.6] years) were included, 133 (22.9%) revisited the ED within 30 days from discharge. Six factors (chronic kidney disease, chronic heart failure, visit to an ED in the preceding 3 months, high anticholinergic burden, DRPs associated with heparin, and safety-related DRPs) were identified as risk factors and combined into a final score, termed the DREAMER score. The model reached an area under the receiver operating curve values of 0.72 (95% confidence interval [CI] = 0.67-0.77) in the referral cohort and 0.71 (95% CI = 0.65-0.74) in the validation cohort (P = .273). Three risk categories were generated, with the following scores and estimated risks: low risk (0-8 points): 11.6%; intermediate risk (9-14 points): 21.3%; and high risk (>14 points): 41.2%. Conclusion and Relevance: The DREAMER score identifies patients at high risk for ED revisit within 30 days from the first visit for a DRPs, being a useful tool to prioritize interventions on discharge.

The usefulness of measuring the anion gap in diagnosing metformin-associated lactic acidosis: a case series.

BACKGROUND: Metformin-associated lactic acidosis (MALA) is a widely documented adverse event of metformin. Despite being considered one of the main causes of metabolic acidosis, the association between an anion gap and MALA diagnosis is still uncertain. CASE PRESENTATION: Cases involving six Caucasian patients with suspected MALA who were admitted to the emergency department were analysed. All these patients presented with pH values < 7.35, lactate levels > 2 mmol/L, and estimated glomerular filtration < 30 mL/min. Metformin plasma concentrations were > 2.5 mg/L in all the patients. The highest metformin concentrations were not found in the patients with the highest lactate levels. The anion gap values ranged from 12.3 to 39.3, with only two patients exhibiting values > 14. CONCLUSIONS: In patients with MALA, there is a significant variability in the anion gap values, which is not related to the level of metformin accumulation, and therefore, it is doubtful whether measuring anion gaps is useful as an approach for MALA diagnosis.

Anticholinergic burden in patients treated for constipation in an emergency department. / Carga anticolinérgica en pacientes atendidos por estreñimiento en un servicio de ugencias.

OBJECTIVES: To evaluate the anticholinergic burden on discharge of patients treated for constipation in an emergency department (ED) and to assess the effect on emergency revisiting within 30 days. MATERIAL AND METHODS: Observational retrospective cohort study. We collected cases with a discharge diagnosis of constipation after ED treatment between September 2018 and June 2019 and recorded information on all drugs taken and the anticholinergic burden of treatment. A revisit to the ED within 30 days was the primary outcome. RESULTS: We included 104 patients. A high anticholinergic burden of treatment was identified in 47 (56.6%), an intermediate burden in 30 (36.1%), and a low burden in 6 (7.2%). Twenty-nine (27.9%) patients revisited the ED within 30 days of discharge. An intermediate anticholinergic burden (23 patients [31.1%] vs 4 [13.3%]; P = .061) and high burden (19 [40.4%] vs 8 [14.1%]; P = .002] was associated with revisiting within 30 days in the univariate analysis. On multivariate analysis, a high anticholinergic burden was independently associated with a higher rate of revisiting than a low burden: adjusted odds ratio (aOR), 4.21; 95% CI, 1.07-16.5; P = .039. An intermediate load was not associated with more revisits, however: aOR, 1.27; 95% CI, 0.25-6.41; P = .776. Prescription of long-term treatment with laxatives on discharge did not reduce revisiting withing 30-days in the group with a high anticholinergic load (OR, 0.86; 95% CI, 0.48-3.27; P = .526), but it did have an effect in patients an intermediate burden (OR, 0.13; 95% CI, 0.02-0.99; P = .049). CONCLUSION: The prescription of drugs leading to a high anticholinergic burden was a factor associated with ED revisits within 30 days in patients treated for constipation.

OBJETIVO: Evaluar la frecuencia e impacto de la carga anticolinérgica del tratamiento en la reconsulta a los 30 días en los pacientes atendidos por estreñimiento en un servicio de urgencias (SU). METODO: Estudio observacional de cohortes retrospectivo. Se incluyeron por oportunidad pacientes que fueron dados de alta con diagnóstico de estreñimiento desde un SU entre septiembre 2018 y junio 2019. Se recogieron los fármacos y su carga anticolinérgica. La variable de resultado fue la reconsulta por cualquier causa a los 30 días. RESULTADOS: Se incluyeron 104 pacientes, 47 (56,6%) se clasificaron como tratamiento con alta carga colinérgica, 30 (36,1%) intermedia y 6 (7,2%) baja. Veintinueve (27,9%) pacientes sufrieron una reconsulta a urgencias en los primeros 30 días tras el alta. Los pacientes con fármacos con una carga anticolinérgica alta tuvieron una mayor frecuencia de reconsultas a 30 días [19/47 (40,4%) vs 8/57 (14,1%); p = 0,002]. Tras el análisis multivarible, en comparación con aquellos con tratamiento con baja carga anticolinérgica, el tener una alta carga (ORa = 4,21; IC 95% 1,07-16,5; p = 0,039), pero no intermedia (ORa = 1,27; IC 95% 0,25-6,41; p = 0,776), se asoció de forma independiente con una mayor reconsulta a los 30 días. La prescripción de laxantes crónicos al alta no redujo la reconsulta a 30 días en el grupo con alta carga anticolinérgica (OR = 0,86; IC 95% 0,48-3,27; p = 0,526), pero sí en aquellos con carga intermedia (OR = 0,13; IC 95% 0,02-0,99; p = 0,049). CONCLUSIONES: La prescripción de fármacos con alta carga anticolinérgica fue un factor asociado con reconsulta a los 30 días en los pacientes atendidos por estreñimiento en urgencias.

Recreational drugs and HIV in Europe: current use of recreational drugs and principal HIV guidelines related recommendations.

INTRODUCTION: Recreational drug consumption has been associated with both higher rates of risk activities related to HIV transmission and also worse adherence and management of HIV patients under HAART treatment. Moreover, relevant interactions may be present in patients under HAART treatment. Our aim is to present the European trends of drug consumption per country and age groups and assess the way drug consumption is addressed in general HIV guidelines. MATERIALS AND METHODS: Last 12-month prevalence drug use was obtained from the European Monitoring Centre for Drugs and Drug Addiction for the four most consumed drugs (cannabis, cocaine, amphetamines, ecstasys). Consumption rates were collected and analyzed by country and age. Principal HIV guidelines were assessed to identify the degree of incorporation of drug use issues at three levels: transmission risk, adherence to the HAART and management of interactions. GUIDELINES: (a) WHO; (b) EACS; (c) BHIVA; (d) US DHHS; (e) IAS-USA; (f) GESIDA; (g) French CPG; (h) Italian CPG. RESULTS: Data on drugs of abuse consumption was obtained from 29 European countries, with results showing relevant drug utilization in Europe. Cannabis was the most frequent drug across all countries, with 10 countries over 5% of prevalence over the last year. Other drugs prevalence accounted for about 0.5-1%, reaching up to: 2.1% for cocaine in Spain, 1.4% for ecstasy in the Netherlands and 1.1% for amphetamines in Estonia. 15-24 and 25-34 years old subgroups had the highest prevalence, although notable use of cannabis and cocaine was also found in the 35-44 and 45-54 subgroups. From the eight guidelines assessed, six considered recreational drugs at any point. Recommendations for specific drugs were given in 50% of the guidelines. From those guidelines addressing drug consumption: three assessed risk habits which related to transmission risk, six appraised issues on adherence to HAART and five comprised data on interactions between recreational drugs and HAART. Additionally, five guidelines mentioned drugs in the context of other issues, such as sexual dysfunction or HIV-associated neurocognitive impairment. CONCLUSIONS: Use of recreational drugs is frequent in Europe, not only in the younger population but also in other unexpected older subgroups. The scarce information found in the guidelines has a potential implication for patients and clinicians; therefore, there is a need to include specific recommendations about the clinical management of people living with HIV who use recreational drugs.