Creatinine-based renal function estimates and dosage of postoperative pain management for elderly acute hip fracture patients

Many analgesics and their metabolites are renally excreted. The widely used Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)-estimated glomerular filtration rate (eGFR) equations are not developed for use in the elderly, while the recent Berlin Initiative Study (BIS), Full Age Spectrum (FAS), and Lund-Malmö revised (LMR) equations are. This observational study investigated differences between creatinine-based eGFR equations and how the choice of equation influences dosage of analgesics in elderly (≥70 years) patients admitted with acute hip fracture. eGFR was calculated by the CKD-EPI, BIS, Cockcroft-Gault (CG), FAS, LMR, and Modification of Diet in Renal Disease (MDRD) equations. Standard daily dose for postoperative pain medications ibuprofen, morphine and gabapentin was simulated for each equation according to dosage recommendations in Renbase®. For 118 patients, mean eGFR from the CKD-EPI, BIS, CG, FAS, LMR, and MDRD equations was 67.3 mL/min/1.73 m2, 59.1 mL/min/1.73 m2, 56.9 mL/min/1.73 m2, 60.3 mL/min/1.73 m2, 58.9 mL/min/1.73 m2, and 79.1 mL/min/1.73 m2, respectively (p < 0.0001). Mean difference to CKD-EPI was −10.4 mL/min/1.73 m2 to 11.8 mL/min/1.73 m2. Choice of eGFR equation significantly influenced the recommended dose (p < 0.0001). Shifting to BIS, FAS, or LMR equations led to a lower recommended dose in 20% to 31% of patients. Choice of eGFR equation significantly influenced dosing of ibuprofen, morphine, and gabapentin

Impact of the early COVID-19 pandemic on adult mental health-related dispensed medications, hospitalizations and specialist outpatient visits in Norway and Sweden:Interrupted time series analysis

AIMS: Norway and Sweden had different early pandemic responses that may have impacted mental health management. The aim was to assess the impact of the early COVID-19 pandemic on mental health-related care.METHODS: We used national registries in Norway and Sweden (1 January 2018-31 December 2020) to define 2 cohorts: (i) general adult population; and (ii) mental health adult population. Interrupted times series regression analyses evaluated step and slope changes compared to prepandemic levels for monthly rates of medications (antidepressants, antipsychotics, anxiolytics, hypnotics/sedatives, lithium, opioid analgesics, psychostimulants), hospitalizations (for anxiety, bipolar, depressive/mood, eating and schizophrenia/delusional disorders) and specialist outpatient visits.RESULTS: In Norway, immediate reductions occurred in the general population for medications (-12% antidepressants to -7% hypnotics/sedatives) except for antipsychotics; and hospitalizations (-33% anxiety disorders to -17% bipolar disorders). Increasing slope change occurred for all medications except psychostimulants (+1.1%/month hypnotics/sedatives to +1.7%/month antidepressants); and hospitalization for anxiety disorders (+5.5%/month), depressive/mood disorders (+1.7%/month) and schizophrenia/delusional disorders (+2%/month). In Sweden, immediate reductions occurred for antidepressants (-7%) and opioids (-10%) and depressive/mood disorder hospitalizations (-11%) only with increasing slope change in psychostimulant prescribing of (0.9%/month). In contrast to Norway, increasing slope changes occurred in specialist outpatient visits for depressive/mood disorders, eating disorders and schizophrenia/delusional disorders (+1.5, +1.9 and +2.3%/month, respectively). Similar changes occurred in the pre-existing mental health cohorts.CONCLUSION: Differences in early COVID-19 policy response may have contributed to differences in adult mental healthcare provision in Norway and Sweden.</p

Investigation of the potential association between the use of fluoxetine and occurrence of acute pancreatitis: a Danish register-based cohort study

BACKGROUND: There is currently conflicting evidence of the association between the use of selective serotonin reuptake inhibitors (SSRIs) and acute pancreatitis. The SSRI fluoxetine has been suspected to be the driver of this serious outcome. Therefore, this study aims to investigate the potential association between fluoxetine use and the occurrence of acute pancreatitis. METHODS: We conducted a nationwide cohort study using Danish register-based data from 1996 to 2016. The exposed group were new users of fluoxetine (1-year washout). The control subjects were new users of citalopram or SSRIs, excluding fluoxetine. The outcome was an incident diagnosis of acute pancreatitis with a 5-year washout. We used an intention-to-treat approach following patients for a maximum of 6 months. Cox regression analyses were performed, estimating hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for age/sex, comorbidities and co-medications, using propensity score adjustment and matching. RESULTS: In the propensity score-matched analyses, 61 783 fluoxetine users were included. The incidence rates among users of fluoxetine and other SSRIs were 5.33 (3.05-8.66) and 5.36 (3.06-8.70) per 10 000 person-years, respectively. No increased risk of acute pancreatitis was identified following fluoxetine exposure compared with either citalopram [HR 1.00, 95% CI 0.50-2.00) or other SSRIs (0.76, 0.40-1.46). CONCLUSIONS: Fluoxetine use was not associated with an increased risk of acute pancreatitis compared with citalopram or other SSRIs. The absolute risk of acute pancreatitis was low and did not vary between different SSRIs. Further research is needed to determine whether there is a class effect on the risk of acute pancreatitis

Surveillance of Antidepressant Safety (SADS): Active Signal Detection of Serious Medical Events Following SSRI and SNRI Initiation Using Big Healthcare Data

INTRODUCTION: The current process for generating evidence in pharmacovigilance has several limitations, which often lead to delays in the evaluation of drug-associated risks. OBJECTIVES: In this study, we proposed and tested a near real-time epidemiological surveillance system using sequential, cumulative analyses focusing on the detection and preliminary risk quantification of potential safety signals following initiation of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). METHODS: We emulated an active surveillance system in an historical setting by conducting repeated annual cohort studies using nationwide Danish healthcare data (1996-2016). Outcomes were selected from the European Medicines Agency's Designated Medical Event list, summaries of product characteristics, and the literature. We followed patients for a maximum of 6 months from treatment initiation to the event of interest or censoring. We performed Cox regression analyses adjusted for standard sets of covariates. Potential safety signals were visualized using heat maps and cumulative hazard ratio (HR) plots over time. RESULTS: In the total study population, 969,667 new users were included and followed for 461,506 person-years. We detected potential safety signals with incidence rates as low as 0.9 per 10,000 person-years. Having eight different exposure drugs and 51 medical events, we identified 31 unique combinations of potential safety signals with a positive association to the event of interest in the exposed group. We proposed that these signals were designated for further evaluation once they appeared in a prospective setting. In total, 21 (67.7%) of these were not present in the current summaries of product characteristics. CONCLUSION: The study demonstrated the feasibility of performing epidemiological surveillance using sequential, cumulative analyses. Larger populations are needed to evaluate rare events and infrequently used antidepressants

Incidence of hospital contacts with acute kidney injury after initiation of second-generation antipsychotics in older adults:a Danish population-based cohort study

PURPOSE: To investigate the association between acute kidney injury (AKI) and use of second-generation antipsychotics (SGA) in older adults. METHODS: In a population-based cohort study using Danish national registries, new users of SGAs (aged ≥ 65) were identified during 2005–2015. Each SGA user was matched to 10 population controls on age, sex, and the SGA initiation date. The outcome was incident AKI within 90 days after the index date. Cox regression was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs), adjusting for potential confounders. RESULTS: In the study, 36,581 new SGA users and 365,810 controls were included. The 90-day incidence rate of AKI was 4.38 and 1.70 per 1000 person-years among SGA users and controls, respectively, corresponding to a crude HR of 2.57 (1.79–3.68). The fully adjusted HR (aHR) was 1.43 (0.89–2.27) for all SGAs. The risk differed among individual drugs with aHRs for olanzapine 3.50 (1.20–10.23), quetiapine 1.62 (0.81–3.26), and risperidone 0.68 (0.28–1.64). In sensitivity analyses, the aHR declined to 1.24 (0.95–1.61) at 1-year follow-up. CONCLUSIONS: Olanzapine use was associated with a significantly increased 90-day AKI risk. For quetiapine, the risk was elevated but not significant, and risperidone had no association. CIs were wide and confounder adjustment largely impacted the estimates. Main limitations included residual confounding and incomplete recording of AKI diagnoses. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00228-022-03339-6

Surveillance of Antidepressant Safety (SADS): Active Signal Detection of Serious Medical Events Following SSRI and SNRI Initiation Using Big Healthcare Data

INTRODUCTION: The current process for generating evidence in pharmacovigilance has several limitations, which often lead to delays in the evaluation of drug-associated risks. OBJECTIVES: In this study, we proposed and tested a near real-time epidemiological surveillance system using sequential, cumulative analyses focusing on the detection and preliminary risk quantification of potential safety signals following initiation of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). METHODS: We emulated an active surveillance system in an historical setting by conducting repeated annual cohort studies using nationwide Danish healthcare data (1996-2016). Outcomes were selected from the European Medicines Agency's Designated Medical Event list, summaries of product characteristics, and the literature. We followed patients for a maximum of 6 months from treatment initiation to the event of interest or censoring. We performed Cox regression analyses adjusted for standard sets of covariates. Potential safety signals were visualized using heat maps and cumulative hazard ratio (HR) plots over time. RESULTS: In the total study population, 969,667 new users were included and followed for 461,506 person-years. We detected potential safety signals with incidence rates as low as 0.9 per 10,000 person-years. Having eight different exposure drugs and 51 medical events, we identified 31 unique combinations of potential safety signals with a positive association to the event of interest in the exposed group. We proposed that these signals were designated for further evaluation once they appeared in a prospective setting. In total, 21 (67.7%) of these were not present in the current summaries of product characteristics. CONCLUSION: The study demonstrated the feasibility of performing epidemiological surveillance using sequential, cumulative analyses. Larger populations are needed to evaluate rare events and infrequently used antidepressants

Differences in Kidney Function Estimates Based on Creatinine and/or Cystatin C in Non-Traumatic Amputation Patients and Their Impact on Drug Prescribing

Accurate kidney function estimates are necessary when prescribing renally-eliminated medications. Our objectives were to investigate how amputation affects estimated glomerular filtration rate (eGFR) and to determine if dosing recommendations differ among different eGFR equations. In a cohort study of non-traumatic amputation patients, eGFR based on creatinine and/or cystatin C were measured before and after amputation. Prescribed, renally-eliminated medications were compared with dosing guidelines in Renbase&reg;. Data from 38 patients with a median age of 75 years were analyzed. The median (range) eGFR was 65 (15&ndash;103), 38 (13&ndash;79), and 48 (13&ndash;86) mL/min/1.73 m2 before amputation and 80 (22&ndash;107), 51 (13&ndash;95), and 62 (16&ndash;100) mL/min/1.73 m2 after amputation for eGFRCreatinine, eGFRCystatinC, and eGFRCombined, respectively (p &lt; 0.01). From before to after amputation, eGFR increased on average by 8.5, 6.1, and 7.4 mL/min/1.73 m2 for eGFRCreatinine, eGFRCystatinC, and eGFRCombined (all p &lt; 0.01), respectively. At least one renally-eliminated medication was prescribed at a higher dose than recommended in 37.8% of patients using eGFRCystatinC, 17.6% using eGFRCombined and 10.8% using eGFRCreatinine. In conclusion, amputation affects eGFR regardless of the eGFR equations. The differences among equations would impact prescribing of renally-eliminated medications, particularly when switching from creatinine to cystatin C

Investigation of the potential association between the use of fluoxetine and occurrence of acute pancreatitis: a Danish register-based cohort study

BACKGROUND: There is currently conflicting evidence of the association between the use of selective serotonin reuptake inhibitors (SSRIs) and acute pancreatitis. The SSRI fluoxetine has been suspected to be the driver of this serious outcome. Therefore, this study aims to investigate the potential association between fluoxetine use and the occurrence of acute pancreatitis. METHODS: We conducted a nationwide cohort study using Danish register-based data from 1996 to 2016. The exposed group were new users of fluoxetine (1-year washout). The control subjects were new users of citalopram or SSRIs, excluding fluoxetine. The outcome was an incident diagnosis of acute pancreatitis with a 5-year washout. We used an intention-to-treat approach following patients for a maximum of 6 months. Cox regression analyses were performed, estimating hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for age/sex, comorbidities and co-medications, using propensity score adjustment and matching. RESULTS: In the propensity score-matched analyses, 61 783 fluoxetine users were included. The incidence rates among users of fluoxetine and other SSRIs were 5.33 (3.05-8.66) and 5.36 (3.06-8.70) per 10 000 person-years, respectively. No increased risk of acute pancreatitis was identified following fluoxetine exposure compared with either citalopram [HR 1.00, 95% CI 0.50-2.00) or other SSRIs (0.76, 0.40-1.46). CONCLUSIONS: Fluoxetine use was not associated with an increased risk of acute pancreatitis compared with citalopram or other SSRIs. The absolute risk of acute pancreatitis was low and did not vary between different SSRIs. Further research is needed to determine whether there is a class effect on the risk of acute pancreatitis

Adherence to Direct Oral Anticoagulants in Patients With Non-Valvular Atrial Fibrillation : A Cross-National Comparison in Six European Countries (2008-2015)

To describe and compare the adherence to different direct oral anticoagulants (DOACs) in eight European databases representing six countries. Longitudinal drug utilization study of new users (≥18 years) of DOACs (dabigatran, rivaroxaban, apixaban) with a diagnosis of non-valvular atrial fibrillation (2008-2015). Adherence was examined by estimating persistence, switching, and discontinuation rates at 12 months. Primary non-adherence was estimated in BIFAP and SIDIAP databases. The highest persistence rate was seen for apixaban in the CPRD database (81%) and the lowest for dabigatran in the Mondriaan database (22%). The switching rate for all DOACs ranged from 2.4 to 13.1% (Mondriaan and EGB databases, respectively). Dabigatran had the highest switching rate from 5.0 to 20.0% (Mondriaan and EGB databases, respectively). The discontinuation rate for all DOACs ranged from 16.0 to 63.9% (CPRD and Bavarian CD databases, respectively). Dabigatran had the highest rate of discontinuers, except in the Bavarian CD and AOK NORDWEST databases, ranging from 23.2 to 64.6% (CPRD and Mondriaan databases, respectively). Combined primary non-adherence for examined DOACs was 11.1% in BIFAP and 14.0% in SIDIAP. There were differences in population coverage and in the type of drug data source among the databases. Despite the differences in the characteristics of the databases and in demographic and baseline characteristics of the included population that could explain some of the observed discrepancies, we can observe a similar pattern throughout the databases. Apixaban was the DOAC with the highest persistence. Dabigatran had the highest proportion of discontinuers and switchers at 12 months in most databases (EMA/2015/27/PH)

Risk of major bleeding associated with the use of direct oral anticoagulants compared to vitamin K antagonists in patients with atrial fibrillation: A European multicountry population-based cohort study

Background: Non-Valvular Atrial fibrillation (NVAF) is one of the most common cardiac rhythm disorders. The introduction of direct oral anticoagulants (DOACs) has broadened the treatment arsenal for NVAF compared to the traditional vitamin K antagonists (VKAs), but observational studies on the benefit-risk balance of DOACs vs VKAs are needed. Objectives: To characterize the risk of major bleeding in DOAC users in a real-world setting using longitudinal data collected in four electronic health care databases from different EU countries. Methods: A cohort study was conducted among new users (≥18 years) of DOACs or VKAs with NVAF using electronic health care data from the United Kingdom (UK; CPRD), Spain (BIFAP), Germany (AOK) and Denmark (Danish National Registers). The incidence of major bleeding events (both overall and by site) and any stroke was compared between periods of current use of DOACs and VKAs. Cox regression analysis was used to estimate hazard ratios (HR) with 95% confidence intervals (CI) and adjust for confounders. Several sensitivity analyses were performed (changing permissible gap length between prescriptions, using hospital admissions only, excluding certain bleeding sites). Results: In total 251,719 patients were included in the four study cohorts (mean age ~75 years,%females between 41.3 and 54.3%), with overall HRs of major bleeding risk for DOACs vs VKAs ranging between 0.84 (95% CI: 0.79-0.90) in Denmark and 1.13 (95% CI 1.02-1.25) in the UK. When stratifying according to bleeding site, the risk of gastrointestinal (GI) bleeding (the majority of events) was statistically significant increased by 48-67% in dabigatran (DBG) users and 30-50% for rivaroxaban (RIV) users compared to VKA users in all data sources except Denmark. The risk of any stroke was increased for RIV (HR 1.78, 95% CI 1.29-2.44) and apixaban (APX, HR 2.20, 95% CI: 1.45- 3.30) vs VKAs in the UK. Sensitivity analyses did not yield substantially different results. Conclusions: Compared to VKAs, APX was not associated with an increased risk of GI bleeding in all data sources and seemed to be have with the lowest risk of any major bleeding events vs VKAs when compared to DBG and RIV. An increased risk of stroke was seen in the UK. Differences in risk estimates obtained in randomized controlled trials and other observational studies with this study could be partially due to design (e.g. patient selection, dealing with drug discontinuation) and definition choices (e.g. outcome coding) and ask for more transparency in methods used