Medication-overuse headache: A pharmacovigilance study in France.

BACKGROUND: Overusing medication for primary headaches or other medical conditions can lead to dependency and medication-overuse headache (MOH) as an adverse drug reaction (ADR). OBJECTIVES: To analyse reports of ADRs associated with MOH recorded in the French national pharmacovigilance database (FPVD). METHODS: This retrospective study selected all MOH cases reported in the FPVD from January 2000 to June 2023. A search of the High-Level Group Term "headache" was performed for drugs classified under ATC codes for the musculoskeletal and nervous systems. Specific keywords were searched in report narratives to further reduce their number. Voluntary intoxication reports were excluded. Only MOH cases according to the International Classification of Headache Disorders or with a medical diagnosis of MOH were considered. RESULTS: Among the 2674 reports associated with the HLGT "headache", for 649 ATC drug codes, only 234 reports correspond to MOH, primarily notified by physicians. The median age was 45 years (IQR: 32-56), with 74.4% females and approximately 61.0% having pre-existing primary headaches. In all, 53.4% of the reports were classified as serious. Among patients, 84.2% had an isolated "headache" as the ADR. One drug was suspected in 47.4% of cases, two drugs in 29.1%, and three or more in 23.5%. In total, 473 suspected drugs, corresponding to 104 active ingredients, were involved, including analgesics (63.0%), in particular, acetaminophen-containing drugs, opioids, triptans and ergots, and non-steroidal anti-inflammatory drugs (12.7%). Antiepileptics and psycholeptics were found in 6.6% and 6.1% of cases, respectively. Drug withdrawal was successful in 84.6% of drug-discontinuation cases. Warnings about MOH are mentioned in the summary of product characteristics (SmPCs) for triptans, ergots, and certain acetaminophen-containing drugs, but not other drug classes. CONCLUSIONS: Certain drug classes show a high reporting rate of MOH and caution should be exercised when prescribing these drugs. Notably, warnings about MOH must be mentioned in the SmPC of all concerned drug classes.

Statin therapy and the incidence of atherosclerotic cardiovascular events after kidney transplantation.

BACKGROUND: Statins are recommended in kidney transplant recipients (KTRs) - a population with a high risk of major cardiovascular (CV) events. However, the literature data on the effectiveness of statins in KTRs are sparse and inconclusive. The present study's objective was to evaluate the association between statin exposure and atherosclerotic CV events in KTRs and the biochemical effectiveness of statins on the lipid profile. METHODS: 318 consecutive KTRs managed at a single center between 2006 and 2019 were retrospectively included. Those exposed to statins after transplantation were incident users. In all users, statins were indicated for primary CV prevention. Lipid profiles, the occurrence of any atherosclerotic CV events (stroke, myocardial infarction, other atherosclerotic CV events, and atherosclerotic CV deaths) were documented comprehensively. We applied Cox models that included statin exposure as a time-dependent covariate fitted with time-varying inverse probability treatment weighting (IPTW) to assess the effectiveness of statins on atherosclerotic CV events and on all CV events. We built linear mixed models to assess the biochemical effectiveness of statins. RESULTS: During a median [interquartile range] follow-up period of 6.0 [3.9-10.0] years, 27 atherosclerotic CV events occurred in 26 patients. In the Cox models fitted with time-varying IPTW, exposure to statins was not associated with a decrease in atherosclerotic CV events; the hazard ratio (HR) [95% confidence interval (CI)] was 1.16 [0.53-2.53] (p=0.700). In the linear mixed models, statin exposure was associated with significant decrease over time in triglyceride and low-density lipoprotein cholesterol concentrations (p < 0.001). These results were consistent when stratified for the intensity of statin therapy. CONCLUSION: Even though the lipid profile improved, statin exposure was not associated with a decrease in CV events in this real-life, single-center, retrospective, long-term follow-up study of a KTR cohort. Larger, controlled studies are needed to confirm or refute these results.

Drugs associated with incident fragility fractures in kidney transplant recipients.

Background: The risk of fragility fractures is high in kidney transplant recipients, and steroids are reportedly a major cause. Other drugs known to induce fragility fractures have been studied in the general population but not in kidney transplant recipients. Here, we investigated the association between exposure over time to drugs that can injure bone (namely vitamin K antagonists, insulin, loop diuretics, proton pump inhibitors, opioids, selective serotonin reuptake inhibitors, antiepileptics and benzodiazepines) and incident fractures and changes over time in T-scores in this population. Methods: A total of 613 consecutive kidney transplant recipients were included between 2006 and 2019. Drug exposures and incident fractures during the study period were comprehensively documented, and dual-energy X-ray absorptiometry was performed regularly. The data were analyzed using Cox proportional hazards models with time-dependent covariates and linear mixed models. Results: Incident fractures occurred in 63 patients, giving a fracture incidence of 16.9 per 1000 person-years. Exposures to loop diuretics [hazard ratio (95% confidence interval) 2.11 (1.17-3.79)] and opioids [5.94 (2.14-16.52)] were associated with incident fractures. Exposure to loop diuretics was associated with a decrease over time in the T-score for the lumbar spine (P = .022) and for the wrist (P = .028). Conclusions: This study suggests that the exposure to loop diuretics and opioids increases the risk of fracture in kidney transplant recipients.

[COVID-19 and adenovirus vaccines: French experience of enhanced pharmacovigilance]. / COVID-19 et vaccins à adénovirus : expérience française de suivi renforcé de pharmacovigilance.

As part of the COVID-19 vaccination campaign, the National Agency for the Safety of Medicines and Health Products and all 31 regional pharmacovigilance centers were mobilized in an exceptional reinforced vaccine pharmacovigilance surveillance system. Concerning adenovirus vaccines, Vaxzévria® and Jcovden®, this national system, based on the daily analysis of notified cases of adverse events, has allowed the early identification of safety signals, some of which have been validated, others still under analysis, common to mRNA vaccines or more specific of adenovirus vaccines such as Vaccine Induced Immune Thrombocytopenia. Complementing european and international actions, this follow-up has contributed to a better definition of the safety profile of these vaccines and has led to redefine the vaccine strategy in our country. Although today these two vaccines have no longer place in the national vaccine strategy, they are still used in other countries, where the experience acquired could be useful and will contribute to fuel the reflection on future therapies involving viral vectors.

Fetal and Neonatal Adverse Drug Reactions Associated with Biologics Taken During Pregnancy by Women with Autoimmune Diseases: Insights from an Analysis of the World Health Organization Pharmacovigilance Database (VigiBase®).

INTRODUCTION: Published data on the safety of biologics other than tumor necrosis factor (TNF) inhibitors during pregnancy are limited. OBJECTIVE: The aim was to detect pharmacovigilance signals for fetal and neonatal adverse drug reactions (ADRs) to biologics taken by pregnant women with autoimmune diseases. METHODS: We performed a disproportionality analysis of the World Health Organization's VigiBase® pharmacovigilance database from 1968 to June 1, 2021. Data were collected in June 2021. By using terms for different hierarchical levels of the Medical Dictionary for Regulatory Activities, we selected the following fetal or neonatal ADRs: stillbirth, premature birth, low birth weight, small for gestational age, and congenital malformations. The frequency of all identified ADRs for biologics of interest (adalimumab, infliximab, golimumab, certolizumab, etanercept, anakinra, canakinumab, tocilizumab, sarilumab, ustekinumab, guselkumab, secukinumab, ixekizumab, belimumab, abatacept, and rituximab) was compared with that of all other reports for all other drugs and quoted as the reporting odds ratio (ROR) [95% confidence interval]. Reports with known concomitant use of teratogenic drugs were excluded from the main analysis. Other analyses included ROR stratifications by therapeutic indication in the periods 1968-2021 and 2001-2021, and an analysis after excluding reports with steroids. RESULTS: In the main analysis, the RORs were particularly high for musculoskeletal malformations with anakinra (7.18 [3.50-14.73]), canakinumab (19.54 [12.82-29.79]), and abatacept (5.09 [2.77-9.33]), and for immune system disorders with canakinumab (347.88 [217.9-555.50]) and rituximab (9.27 [2.95-29.15]). After the exclusion of reports with steroids, the ROR was significant for neonatal infections with belimumab (28.49 [5.75-141.25]). CONCLUSION: We identified possible associations with some adverse fetal and neonatal outcomes, suggesting that vigilance is required when prescribing certain biologics during pregnancy.

Use of the Capture-Recapture Method to Estimate the Frequency of Community- and Hospital-Acquired Drug-Induced Acute Kidney Injuries in French Databases.

Drug-induced acute kidney injury (AKI) can occur both in primary care (i.e., community-acquired AKI (CA-AKI)) and in hospital settings (i.e., hospital-acquired AKI (HA-AKI)). The reported prevalence of these events varies markedly from one study to another, mainly due to differences in the study design. To estimate the frequency of drug-induced AKIs (both CA-AKIs and HA-AKIs) observed in a French university hospital, we applied the capture-recapture method to 1) the French national pharmacovigilance database (FPVD) and 2) a cohort of hospitalized patients with drug-induced AKIs (documented by analyzing the French national hospital discharge database and the patients' electronic medical records). Drug-induced AKIs were determined according to the Naranjo algorithm and then categorized as CA-AKIs or HA-AKIs. A total number of 1,557 episodes of AKI were record during the study period, of them, the estimated total number of drug-induced AKIs was 593 [95% confidence interval (CI): 485-702], and the estimated prevalence was 38.1% [95%CI: 35.67-40.50]. The prevalences of HA-AKIs and CA-AKIs were similar (39.4% [36.24-42.54] and 37.4% [33.67-41.21], respectively). Only 6.1% of the drug-induced AKIs were recorded in the FPVD, and the proportions of recorded HA-AKIs and CA-AKI differed markedly (3.0% vs. 10.5%, respectively). One of the most frequently involved drug classes were antibiotics in the HA-AKI subgroup (13.0%) and antineoplastics in the CA-AKI subgroup (8.3%). Application of the capture-recapture method to two incomplete data sources can improve the ability to identify and quantify adverse drug reactions like AKIs. The frequency of drug-induced AKI is relatively high and is probably underestimated. The clinical management of an AKI might depend on where it originated.

Guillain-Barré Syndrome Associated with COVID-19 Vaccines: A Perspective From Spontaneous Report Data.

BACKGROUND AND OBJECTIVE: The concern surrounding the association between Guillain-Barré syndrome (GBS) and vaccination has increased with the widespread use of COVID-19 vaccines. The aim of this study was to assess the potential association of GBS with mRNA-based or adenovirus-vectored COVID-19 vaccines. METHODS: Reports of GBS associated with mRNA-based or adenovirus-vectored COVID-19 vaccines were extracted from the WHO pharmacovigilance database, exposure data from the Our World in Data website, and the background rates of GBS from published data. For countries contributing to VigiBase and with available data on COVID-19 vaccine exposure, reporting rates were estimated and observed-to-expected (OE) analyses were performed. RESULTS: A total of 2499 cases were included: 1157 (46.3%) cases with adenovirus-vectored COVID-19 vaccines and 1342 (53.7%) with mRNA-based COVID-19 vaccines. The male-to-female sex ratio was 1.09 and the median (IQR) age was 57 (45-66) years. The reporting rates (95% CI) per 100,000 person-years within the 42-day window were 5.57 (5.13-6.03) for adenovirus-vectored COVID-19 vaccines and 1.39 (1.31-1.47) for mRNA-based COVID-19 vaccines, while the background incidence was 1.2-3.1 per 100,000 person-years. For mRNA-based COVID-19 vaccines, the OE ratio was <1 for both time windows in all European countries and slightly elevated for the 21-day window in the USA. For adenovirus-vectored COVID-19 vaccines, the OE ratio was consistently > 2.0 for all countries. Sensitivity analyses minimally altered these results. CONCLUSIONS: These findings suggest both the absence of safety concern for GBS with mRNA-based COVID-19 vaccines and an increased risk with adenovirus-vectored COVID-19 vaccines. Back to top.

Posterior Reversible Encephalopathy Syndrome After Self-Medication With an Oral Decongestant: A Case Report.

Introduction: Posterior reversible encephalopathy syndrome (PRES) is a rare neurological disorder caused by the dysregulation of cerebral perfusion. Case Presentation: We report on a 18-year-old female patient with a history of end-stage renal disease and thrice weekly hemodialysis. She was admitted to the emergency department with mental confusion, blurred vision, headaches, and vomiting, following self-medication with an oral decongestant containing pseudoephedrine. We observed hypointense lesions with T1-weighted MRI and hyperintense areas with T2-weighted and fluid-attenuated inversion recovery MRI sequences. The lack of diffusion restriction was consistent with a diagnosis of PRES. A concomitant Enterobacter cloacae hemodialysis catheter-bloodstream infection was also diagnosed. We hypothesize that both sepsis and inappropriate self-medication with oral pseudoephedrine contributed to hypertension, endothelial dysfunction, and vasogenic edema. The patient received intensive care and made a full recovery. Discussion: PRES is a life-threatening condition that requires intensive care. Identification of the etiology is the keystone of medical care. Inappropriate self-medication with an oral decongestant might trigger PRES - highlighting the importance of patient education.

Risk factors for and characteristics of community- and hospital-acquired drug-induced acute kidney injuries.

Drugs constitute one of the leading causes of acute kidney injuries (AKIs) and can appear in community (CA-AKI) or hospital (HA-AKI) population. The objectives of the present study of a cohort of hospitalized patients with AKI were to describe the characteristics of drug-induced AKIs and the patients' short-term outcomes and assess risk factors for drug-induced AKIs overall, CA-AKIs, and HA-AKIs. Based on a cohort of 1557 hospitalized patients suffering from AKIs based on PMSI extraction and chart review (IRA-PMSI), drug-induced AKIs were identified by applying the Naranjo adverse drug reaction (ADR) probability scale. Multivariate logistic regression was used to identify factors associated with CA-AKIs and/or HA-AKIs. When considering the 1557 patients who experienced an AKI, 445 (28.6%) of the injuries were drug-induced (180 CA-AKIs (40.4%) and 265 HA-AKIs (59.6%)). Antibiotics, diuretics, and contrast agents were significantly more likely to be involved in HA-AKIs, whereas antineoplastic, lipid-lowering drugs, antidiabetics, and immunosuppressive were significantly more likely to be involved in CA-AKIs. Female sex (odds ratio [OR] [95%CI] = 1.3 [1.04-1.67]), chronic kidney disease (CKD) (OR = 1.8 [1.40-2.67]), and a history of ADRs of any type (OR = 1.3 [1.05-1.73]) were significant risk factors for drug-induced AKIs. CKD was a risk factor for both CA-AKI and HA-AKI. In view of the long-term impact of AKI on the kidneys and the differences between our CA-AKI and HA-AKI subgroups, our present results are interesting for optimizing treatments, limiting the occurrence of CA- and HA-AKIs and (ultimately) reducing healthcare costs.

COVID-19 in DMARD-treated patients with inflammatory rheumatic diseases: Insights from an analysis of the World Health Organization pharmacovigilance database.

BACKGROUND: To determine whether the use of disease-modifying antirheumatic drugs (DMARDs) is linked to the risk of COVID-19 among patients with inflammatory rheumatic diseases (IRDs). METHODS: We performed a disproportionality analysis of the World Health Organization pharmacovigilance database between January 1, 2020, and June 10, 2020. The frequency of COVID-19 reports for all DMARD classes identified was compared with that for all other reports for all other drugs and quoted as the reporting odds ratio (ROR) (95% confidence interval [CI]). RESULTS: Among 980,446 individual case-safety reports voluntarily recorded in the database, 398 identified COVID-19 in DMARD-treated patients with IRDs. There were 177 (44.5%) patients with rheumatoid arthritis (RA), 120 (30.1%) with ankylosing spondylitis (AS), 93 (23.4%) with psoriatic arthritis (PsA), and 8 (2.0%) with juvenile idiopathic arthritis. Most of the cases of COVID-19 occurred in patients taking anti-TNF agents (84.2%), resulting in a significant disproportionality signal (ROR [95% CI]: 8.31 [7.48-9.23]) - particularly in patients with RA, AS or PsA. A significant inverse disproportionality was found for the anti-IL-6 agent tocilizumab (ROR [95% CI]: 0.12 [0.02-0.88]) and JAK inhibitors (ROR [95% CI]: 0.33 [0.19-0.58]) in patients with RA - suggesting that these two drug classes are safer in the context of RA. CONCLUSION: Our results are in line with the literature on a potentially better safety profile for anti-IL-6 agents and JAK inhibitors. The WHO pharmacovigilance data suggest that COVID-19 is significantly more frequent in patients with IRDs treated with TNF inhibitors.

Potential interactions between uraemic toxins and drugs: an application in kidney transplant recipients treated with calcineurin inhibitors.

BACKGROUND: The uraemic toxins that accumulate as renal function deteriorates can potentially affect drug pharmacokinetics. This study's objective was to determine whether plasma concentrations of certain uraemic toxins are correlated with blood concentrations of two immunosuppressants. METHODS: DRUGTOX was a cross-sectional study of 403 adult patients followed up after kidney transplantation and who had undergone therapeutic drug monitoring (TDM) of calcineurin inhibitors (tacrolimus or cyclosporin) between August 2019 and March 2020. For each patient, immunosuppressant trough concentrations (C0) were measured in whole blood samples and then normalized against the total daily dose (C0:D ratio). The sample was assayed for five uraemic toxins [urea, trimethylamine N-oxide (TMAO), indole acetic acid (IAA), p-cresylsulphate (PCS) and indoxylsulphate (IxS)] using liquid chromatography-tandem mass spectrometry. RESULTS: The median age was 56 years [interquartile range (IQR) 48-66] and the median estimated glomerular filtration rate was 41 mL/min/1.73 m2 (IQR 30-57). Age, sex, body mass index (BMI), urea, IxS and PCS were significantly associated with an increment in the tacrolimus C0:D ratio. A multivariate analysis revealed an independent association with IxS [odds ratio 1.36 (95% confidence interval 1.00-1.85)] after adjustment for sex, age and BMI, whereas adjustment for age weakened the association for PCS and urea. In a univariate logistic analysis, age, sex, BMI and the TMAO level (but not PCS, IxS, IAA or urea) were significantly associated with an increment in the cyclosporine C0:D ratio. CONCLUSIONS: Even though TDM and dose adaptation of immunosuppressants keep levels within the therapeutic window, increased exposure to tacrolimus (but not cyclosporine) is associated with an accumulation of PCS, IxS and urea.

Use of a hospital administrative database to identify and characterize community-acquired, hospital-acquired and drug-induced acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) has serious short- and long-term consequences. The objective of the present study of a cohort of hospitalized patients with AKI was to (i) evaluate the proportion of patients with hospital-acquired (HA) AKI and community-acquired (CA) AKI, the characteristics of these patients and the AKIs, and the short-term outcomes, and (ii) determine the performance of several ICD-10 codes for identifying AKI (both CA and HA) and drug-induced AKI. METHODS: A cohort of hospitalized patients with AKI was constituted by screening hospital's electronic medical records (EMRs) for cases of AKI. We distinguished between and compared CA-AKI and HA-AKI and evaluated the proportion of AKIs that were drug-induced. The EMR data were merged with hospital billing codes (according to the International Classification of Diseases, 10th Edition (ICD-10)) for each hospital stay. The ability of ICD-10 codes to identify AKIs (depending on the type of injury) was determined by calculating the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Lastly, we sought to validate specific ICD-10 codes for drug-induced AKI. RESULTS: Of the 2473 patients included, 1557 experienced an AKI (HA-AKI: 59.3%; CA-AKI: 40.7%). Patients with CA-AKI had a better short-term outcome and a lower death rate (7.6%, vs. 20% for HA-AKI). One AKI in three was drug-induced. The combination of AKI codes had a very high specificity (94.8%), a high PPV (94.9%), a moderate NPV (56.7%) and moderate sensitivity (57.4%). The sensitivity was higher for CA-AKI (72.2%, vs. 47.2% for HA-AKI), for more severe AKI (82.8% for grade 3 AKI vs. 43.7% for grade 1 AKI), and for patients with CKD. Use of a specific ICD-10 code for drug-induced AKI (N14x) alone gave a very low sensitivity (1.8%), whereas combining codes for adverse drug reactions with AKI-specific codes increased the sensitivity. CONCLUSION: Our results show that the combination of an EMR-based analysis with ICD-10-based hospital billing codes gives a comprehensive "real-life" picture of AKI in hospital settings. We expect that this approach will enable researchers to study AKI in more depth.

Associations between osteoporosis and drug exposure: A post-marketing study of the World Health Organization pharmacovigilance database (VigiBase®).

BACKGROUND: Bone remodeling is a complex process, and many conditions (including drug exposure) lead to osteoporosis. Here, we sought to detect new disproportionality signals for drugs associated with osteoporosis. METHODS: We performed a disproportionality analysis of the World Health Organization's VigiBase® pharmacovigilance database through April 12, 2020. The frequency of reports on osteoporosis for all identified drug classes was compared with that for all other drugs and quoted as the reporting odds ratio (ROR) [95% confidence interval (CI)]. RESULTS: Of the 7,594,968 cases spontaneously recorded to VigiBase®, 4758 concerned osteoporosis. New disproportionality signals with a pharmacologically plausible mechanism were found for drugs used in neurology (levodopa (ROR [95%CI]: 10.18 [4.33-25.10]), selective serotonin agonists (4.22 [2.34-7.00]) and memantine (4.10 [1.56-8.93])), hematology (romiplostim (4.93 [1.15-21.10])), pulmonology (macitentan (3.02 [1.84-4.90])), ophthalmology (ranibizumab (3.31 [1.00-10.51])) and rheumatology (tofacitinib (3.65 [3.00-4.40])). The robustness of these new results is supported by the significant RORs for the vast majority of drugs already known to induce osteoporosis and/or increase the fracture risk, namely glucocorticoids, gonadotropin-releasing hormone analogs, anti-aromatases, androgen receptor blockers, thyroid hormones, proton pump inhibitors, thiazolidinediones, vitamin K antagonists, loop diuretics, protease inhibitors, nucleoside and nucleotide reverse transcriptase inhibitors, and enzyme-inducing antiepileptics including barbiturates and derivatives, hydantoin derivatives, carboxamide derivatives and fatty acid derivatives. CONCLUSION: We established up a comprehensive list of drugs potentially associated with osteoporosis and highlighted those with pharmacologically plausible mechanisms leading to bone fragility. Our results might pave the way for additional exploration of these mechanisms.

Associations between dysbiosis-inducing drugs, overall survival and tumor response in patients treated with immune checkpoint inhibitors.

BACKGROUND: There are conflicting data on the effects of dysbiosis-inducing drugs, and especially antibiotics (ATBs), on clinical outcomes in patients treated with immune checkpoint inhibitors (ICIs). There is a particular lack of data for patients with melanoma. METHODS: We performed a single-center retrospective study of the associations between ATBs and other drugs known to modify the gut microbiota (proton pump inhibitors, nonsteroidal anti-inflammatory drugs, statins, opioids, anti-vitamin K, levothyroxine, vitamin D3, antiarrhythmics, metformin and phloroglucinol), overall survival (OS) and tumor response in consecutive cancer patients (particularly those with melanoma) treated with an ICI (ipilimumab, nivolumab or pembrolizumab) over a 9-year period. RESULTS: A total of 372 patients were included. The mean ± standard deviation age was 64.0 ± 12.1 years. The most frequently prescribed ICI was nivolumab (in 58.3% of patients) and the most frequent indications were lung cancer (44.6%) and melanoma (29.6%). Overall, 112 patients (30.1%) had received ATBs. ATB use was associated with (1) shorter OS in the study population as a whole [adjusted hazard ratio [95% confidence interval (CI)]: 1.38 (1.00-1.90), p = 0.048] and in patients with melanoma [adjusted hazard ratio (95% CI): 2.60 (1.06-6.39), p = 0.037], and (2) a lower response rate in the study population as a whole [8.1%, versus 31.1% in patients not treated with ATBs; adjusted odds ratio (95% CI): 6.06 (2.80-14.53), p < 0.001] and in patients with melanoma [adjusted odds ratio (95% CI): 4.41 (1.04-22.80), p = 0.045]. Sensitivity analyses that minimized the indication bias did not reveal an association between OS and the presence of an infection requiring ATBs (quantified as the severity of infection, hospitalization for an infection, or ICI discontinuation). Other dysbiosis-inducing drugs were not associated with a difference in OS. CONCLUSION: Unlike other dysbiosis-inducing drugs, ATBs were associated with poorer clinical outcomes in ICI-treated patients overall and in the subset of patients with melanoma.

Impact of the corticosteroid indication and administration route on overall survival and the tumor response after immune checkpoint inhibitor initiation.

BACKGROUND: Based on their indications, systemic corticosteroids appear to negatively affect clinical outcomes in immune checkpoint inhibitor (ICI)-treated patients. There are few data on the influence of topical and inhaled corticosteroids on the ICIs' effectiveness. METHODS: In a single-center study, we retrospectively investigated the impact of systemic corticosteroids according to their indication [an immune-related adverse event (irAE) or another indication] on overall survival (OS) and the tumor response in all consecutive patients after initiation of ipilimumab, nivolumab or pembrolizumab over a 9-year period. The impacts of topical and inhaled corticosteroids were also examined. RESULTS: Three hundred and seventy-two patients were included. The mean ± standard deviation age was 64.0 ± 12.1 years. The most frequently prescribed ICI was nivolumab (in 58.3% of the patients) and the most frequent indications were lung cancer (44.6%) and melanoma (29.6%). Systemic corticosteroid use for an irAE did not have a negative impact on OS [adjusted hazard ratio (HR) [95% confidence interval (CI)] 1.04 (0.56-1.95), p = 0.902] or the best overall tumor response [adjusted odds ratio (OR) (95% CI) 1.69 (0.52-6.56), p = 0.413], while systemic corticosteroid use for another indication was associated with shorter OS [adjusted HR (95% CI) 1.34 (1.05-2.03), p = 0.046] and a poor best overall tumor response [adjusted OR (95% CI) 2.04 (1.07-5.80), p = 0.039] with a cumulative dose cut-off of 3215 mg prednisolone equivalent (specificity 71.4%; sensitivity 65.3%) and a time cut-off of 132 days (specificity 71.4%; sensitivity 89.8%). The use of topical corticosteroids was associated with a longer OS; this was probably due to dermatological irAEs. Inhaled corticosteroid use did not influence OS. CONCLUSION: Systemic corticosteroid use for an irAE does not impact OS or the tumor response, whereas use for other indications (themselves often associated with a worse prognosis) does. Topical and inhaled steroids do not have a negative impact on OS.

Evaluation of Changes Over Time in the Drug Burden and Medication Regimen Complexity in ESRD Patients Before and After Renal Transplantation.

BACKGROUND: Medication regimen complexity (MRC) has not been characterized in detail in patients with end-stage renal disease (ESRD). The objective of the present study was to quantify changes over time in the prescription drug burden and MRC in patients with ESRD (before transplantation, on discharge after kidney transplantation [M0], and 4 months [M4] and 12 months [M12] afterward). METHODS: We retrospectively studied adult patients having undergone kidney transplantation. The number and types of drug prescribed, the pill burden, and the MRC index (MRCI) at 4 different time points (before transplantation, M0, M4, and M12) were extracted from the patients' medical records. MRCI was calculated by adding each drug score (calculated according to its formulation, dosing frequency, and additional instructions concerning administration). Hence, the MRCI took account of all prescription drugs. A logistic regression model was used to identify factors associated with an elevated MRCI at M12. RESULTS: The median (interquartile range) age of the 354 study participants was 52 years (42-62). Respectively 21%, 42%, 53%, and 38% of the patients were taking 10 or more drugs before transplantation and at M0, M4, and M12. At M12, the 3 most frequently prescribed drug classes were immunosuppressants, cardiovascular system drugs, and drugs acting on the alimentary tract and metabolism. The pill burden and MRCI before transplantation were significantly lower (P < 0.001) than at each time point after transplantation. Diabetes and dyslipidemia were independently associated with an elevated MRCI at M12. CONCLUSION: In kidney transplant recipients, the drug burden and MRCI were greater at all time points after transplantation than before transplantation. The impact of the drug burden and MRC on medication adherence and clinical outcomes in these patients requires further evaluation.

Association between renin-angiotensin system inhibitors and COVID-19 complications.

AIMS: To describe the characteristics of patients hospitalized with COVID-19 (including their long-term at-home medication use), and compare them with regard to the course of the disease. To assess the association between renin-angiotensin system inhibitors (RASIs) and disease progression and critical outcomes. METHODS AND RESULTS: All consecutive hospitalized patients with laboratory-confirmed COVID-19 in a university hospital in Amiens (France) were included in this study. The primary composite endpoint was admission to an intensive care unit (ICU) or death before ICU admission. Univariable and multivariable logistic regression models were used to identify factors associated with the composite endpoint. Between 28 February 2020 and 30 March 2020, a total of 499 local patients tested positive for SARS-CoV-2. Of these, 231 were not hospitalized {males 33%; median [interquartile range (IQR)] age: 44 (32-54)}, and 268 were hospitalized [males 58%; median (IQR) age: 73 (61-84)]. A total of 116 patients met the primary endpoint: 47 died before ICU admission, and 69 were admitted to the ICU. Patients meeting the primary endpoint were more likely than patients not meeting the primary endpoint to have coronary heart disease and to have been taking RASIs; however, the two subsets of patients did not differ with regard to median age. After adjustment for other associated variables, the risk of meeting the composite endpoint was 1.73 times higher (odds ratio 1.73, 95% confidence interval 1.02-2.93) in patients treated at baseline with a RASI than in patients not treated with this drug class. This association was confirmed when the analysis was restricted to patients treated with antihypertensive agents. CONCLUSIONS: We highlighted a potential safety signal for RASIs, the long-term use of which was independently associated with a higher risk of severe COVID-19 and a poor outcome. Due to the widespread use of this important drug class, formal proof based on clinical trials is needed to better understand the association between RASIs and complications of COVID-19.

Abnormal laboratory findings and plasma concentration monitoring of lopinavir and ritonavir in COVID-19.

It is not known whether the adverse events (AEs) associated with the administration of lopinavir and ritonavir (LPV/r) in the treatment of COVID-19 are concentration-dependent. In a retrospective study of 65 patients treated with LPV/r and therapeutic drug monitoring (TDM) for severe forms of COVID-19 (median age: 67; males: 41 [63.1%]), 33 (50.8%) displayed a grade ≥2 increase in plasma levels of hepatobiliary markers, lipase and/or triglycerides. A causal relationship between LPV/r and the AE was suspected in 9 of the 65 patients (13.8%). At 400 mg b.i.d., the plasma trough concentrations of LPV/r were high and showed marked interindividual variability (median [interquartile range]: 16,600 [11,430-20,842] ng/ml for lopinavir and 501 [247-891] ng/ml for ritonavir). The trough lopinavir concentration was negatively correlated with body mass index, while the trough ritonavir concentration was positively correlated with age and negatively correlated with prothrombin activity. However, the occurrence of abnormal laboratory values was not associated with higher trough plasma concentrations of LPV/r. Further studies will be needed to determine the value of TDM in LPV/r-treated patients with COVID-19.