Unknown adverse drug reactions from spontaneous reports in a hospital setting: characterization, follow-up, and contribution to the pharmacovigilance system.

Introduction: Post-marketing identification and report of unknown adverse drug reactions (ADRs) are crucial for patient safety. However, complete information on unknown ADRs seldom is available at the time of spontaneous ADR reports and this can hamper their contribution to the pharmacovigilance system. Methods: In order to characterize the seriousness and outcome of unknown ADRs at the time of report and at follow-up, and analyze their contribution to generate pharmacovigilance regulatory actions, a retrospective observational study of those identified in the spontaneous ADR reports of patients assisted at a hospital (January, 2016-December, 2021) was carried out. Information on demographic, clinical and complementary tests was retrieved from patients' hospital medical records. To evaluate the contribution to pharmacovigilance system we reviewed the European Union SmPCs, the list of the pharmacovigilance signals discussed by the Pharmacovigilance Risk Assessment Committee, and its recommendations reports on safety signals. Results: A total of 15.2% of the spontaneous reported cases during the study contained at least one unknown drug-ADR pair. After exclusions, 295 unknown drug-ADR pairs were included, within them the most frequently affected organs or systems were: skin and subcutaneous tissue (34, 11.5%), hepatobiliary disorders (28, 9.5%), cardiac disorders (28, 9.5%) and central nervous system disorders (27, 9.2%). The most frequent ADRs were pemphigus (7, 2.4%), and cytolytic hepatitis, sudden death, cutaneous vasculitis and fetal growth restriction with 6 (2%) each. Vaccines such as covid-19 and pneumococcus (68, 21.3%), antineoplastics such as paclitaxel, trastuzumab and vincristine (39, 12.2%) and immunosuppressants such as methotrexate and tocilizumab (35, 11%) were the most frequent drug subgroups involved. Sudden death due to hydroxychloroquine alone or in combination (4, 1.4%) and hypertransaminasemia by vincristine (n = 3, 1%) were the most frequent unknown drug-ADR pairs. A total of 269 (91.2%) of them were serious. Complementary tests were performed in 82.7% of unknown-ADR pairs and helped to reinforce their association in 18.3% of them. A total of 18 (6.1%) unknown drug-ADR pairs were evaluated by the EMA, in 8 (2.7%) the information was added to the drug's SmPC and in 1 case the risk prevention material was updated. Conclusion: Identification and follow-up of unknown ADRs can be of great relevance for patient safety and for the enrichment of the pharmacovigilance system.

Prevalencia de las enfermedades reumáticas en el Baix Empordà / Prevalence of rheumatic diseases in Baix Empordà

Introducción: En España, la prevalencia de diferentes enfermedades reumáticas se conoce principalmente a través de los estudios EPISER coordinados desde la Sociedad Española de Reumatología y que parten de encuestas en una muestra poblacional. Nuestro estudio tiene por objetivo describir la prevalencia en 2016 de las distintas enfermedades reumáticas en la población residente en el Baix Empordà según registros de codificación asistencial. Materiales y métodos: Estudio observacional, descriptivo y transversal realizado sobre la población residente durante los años 2016-2017 en la comarca del Baix Empordà, donde una organización sanitaria integrada (Serveis de Salut Integrats Baix Empordà) gestiona todos los dispositivos asistenciales públicos con un sistema de información unificado. Se seleccionaron los pacientes ≥ 20 años y se analizó la codificación CIE-9-CM de sus contactos asistenciales en función de 11 agrupaciones diagnósticas de 28 enfermedades reumáticas. Las agrupaciones fueron: poliartritis, espondiloartritis, artritis microcristalinas, artrosis (excepto localización vertebral), reumatismos de partes blandas, fibromialgia, dolor vertebral crónico (incluyendo artrosis), osteoporosis, enfermedades del tejido conectivo, vasculitis y otros. La población estudiada se asignó a tres categorías: «con enfermedad reumática», «posible enfermedad reumática» y «sin enfermedad reumática». Resultados: La muestra final fue de 71.785 personas, así distribuidas: «con enfermedad reumática» (n=25.990; 36,2%); «posible enfermedad reumática» (n=4.406; 6,1%) y «sin enfermedad reumática» (n=41.389; 57,7%). El grupo «con enfermedad reumática» mostró un predominio de mujeres (59,8% vs. 44,9%) y mayor edad (59,1±17,7 vs. 45,1±16,2; p<0,001) en comparación al grupo «sin enfermedad reumática». Conclusiones: El 36,2% de nuestra población presenta algún tipo de enfermedad reumática.(AU)

Background: In Spain, the prevalence of different rheumatic diseases is known mainly through the EPISER studies coordinated by the Spanish Society of Rheumatology and based on surveys in a population sample. The aim of our study is to describe the prevalence in 2016 of different rheumatic diseases in the population residing in Baix Empordà according to healthcare coding records. Materials and methods: Observational, descriptive and cross-sectional study carried out on the population attended from 2016-2017 in Serveis de Salut Integrats del Baix Empordà, an organizational service that includes all the healthcare facilities in the Baix Empordà area with a unique information system. Patients ≥ 20 years of age were selected and the ICD9-CM coding of all their healthcare contacts was analysed according to 11 entities and 28 diseases. The entities were: polyarthritis, spondyloarthritis, microcrystalline arthritis, osteoarthritis, soft tissue rheumatism, fibromyalgia, chronic spinal pain, osteoporosis, connective tissue diseases, vasculitis and others. The studied population was assigned to the categories: “with rheumatic disease”, “possible rheumatic disease” and “without rheumatic disease”. Results: In total, 71,785 patients were distributed as: 36.2% “with rheumatic disease (n=25,990); 6.1% with “possible rheumatic disease” (n=4,406) and 57.7% “without rheumatic disease” (n=41,389). The group “with rheumatic disease” showed a predominance of women (59.8% vs. 44.9%) and older age (59.1±17.7 vs. 45.1±16.2; P <.001) compared to the group “without rheumatic disease”. The presence of rheumatic disease increased progressively with age, being maximum in the group between 55-75 years. Conclusions: 36.2% of our population has some type of rheumatic disease.(AU)

Usefulness of ultrasound in the diagnosis of crystal deposition diseases.

Gout and calcium pyrophosphate crystal deposition disease (CPPD) are common forms of inflammatory arthritis whose prevalence has increased in recent years. Although the identification of monosodium urate crystals (MSU) and calcium pyrophosphate crystals (CPP) in synovial fluid (SF) by polarized light microscopy are the gold standard for diagnosing these diseases, SF analysis is not always available. An early diagnosis and specific treatment, especially in gout, allows avoiding irreversible structural damage, comorbidities, and a severe impact on the quality of life of patients. Musculoskeletal ultrasound (US) is a noninvasive tool that allows detecting aggregates of microcrystals at multiple anatomical sites and helps to establish a specific diagnosis. The objective of this review is to evaluate the applications of US in the diagnosis and clinical management of the main microcrystalline arthropathies. The US has helped improve our understanding of the natural history of the disease, due to its ability to visualize not only soft tissue inflammation and structural damage, but also the characteristics of MSU and CPP crystal deposition. The anatomical sites of crystal deposition are also a key factor for differential diagnosis in different microcrystalline diseases. The US allows establishing an early diagnosis, especially in asymptomatic hyperuricemia, to discriminate with other inflammatory diseases, to assess the extent of microcrystalline deposition and their sensitivity to change after treatment. Given its increasing availability in clinical practice and strong evidence, US is a bedside imaging technique helping clinicians to improve diagnosis and therapy monitoring in their daily practice.

Prevalence of rheumatic diseases in Baix Empordà.

BACKGROUND: In Spain, the prevalence of different rheumatic diseases is known mainly through the EPISER studies coordinated by the Spanish Society of Rheumatology and based on surveys in a population sample. The aim of our study is to describe the prevalence in 2016 of different rheumatic diseases in the population residing in Baix Empordà according to healthcare coding records. MATERIALS AND METHODS: Observational, descriptive and cross-sectional study carried out on the population attended from 2016 to 2017 in SIBBE (Serveis de Salut Integrats del Baix Empordà), an organizational service that includes all the healthcare facilities in the Baix Empordà area with a unique information system. Patients ≥ 20 years of age were selected and the ICD9-CM coding of all their healthcare contacts was analysed according to 11 entities and 28 diseases. The entities were: polyarthritis, spondyloarthritis, microcrystalline arthritis, osteoarthritis, soft tissue rheumatism, fibromyalgia, chronic spinal pain, osteoporosis, connective tissue diseases, vasculitis and others. The studied population was assigned to the categories: "with rheumatic disease", "possible rheumatic disease" and "without rheumatic disease". RESULTS: In total, 71,785 patients were distributed as: 36.2% "with rheumatic disease (n = 25,990); 6.1% with "possible rheumatic disease" (n = 4406) and 57.7% "without rheumatic disease" (n = 41,389). The group "with rheumatic disease" showed a predominance of women (59.7% vs. 44.9%) and older age (59.1 ±â€¯17.7 vs. 45.1 ±â€¯16.2; p < .001) compared to the group "without rheumatic disease". The presence of rheumatic disease increased progressively with age, being maximum in the group between 55-75 years. CONCLUSIONS: 36.2% of our population has some type of rheumatic disease. The estimated prevalence of some rheumatic diseases in the Baix Empordà population is partially consistent with that estimated by the EPISER 2016 study. Rheumatic disease affects women in a greater proportion and is more frequent in patients over 45 years of age.

Interobserver reliability of Masei index validation by a multicenter collaborative group of rheumatologists.

MASEI is the main validated ultrasound score for the evaluation of enthesis. The lack of studies facing the agreement to achieve for the interpretation of the MAdrid Sonographic Enthesis Index (MASEI) among researchers from different centers in multicenter studies is of concern. The aim of this multicenter was to evaluate the interobserver reliability of MASEI. An experienced ultrasonographer-rheumatologist performed ultrasound scans of the areas included in MASEI index in three patients with Ankylosing Spondylitis and Psoriatic Arthritis. Videos were captured. The videos were then evaluated by 24 rheumatologists of the ultrasound working group of the Catalan Society of Rheumatology (EcoCAT). A face-to-face training meeting was held. Ten days after the workshop, the study participants evaluated the videos. A reliability assessment was performed. The ICC for the MASEI scores after the workshop was of 0.97 (95% CI 89-99). Reliability did not vary statistically with examiner experience. Globally, no problems of reliability by structures were seen, and all the ICCs were above 0.90 and improved slightly after the educational program. However, the correlation observed between examiners at plantar aponeursis and triceps tendon was weak. The small variability observed in the results of the index validation in our study, suggests that the MASEI index is reproducible by different observers when those are well trained and show awesome results of the enthesis when examined by ultrasound.

Spontaneously Reported Adverse Drug Reactions and Their Description in Hospital Discharge Reports: A Retrospective Study.

The inclusion of spontaneously reported adverse drug reactions (ADRs) in hospital discharge reports was examined, in addition to the factors associated with their inclusion, the resulting therapeutic decisions, and any recommendations made upon patient discharge regarding the suspected offending drugs. ADRs that were spontaneously reported during 2017 and 2018 to the pharmacovigilance program were retrospectively analyzed. Information regarding patient characteristics, drug treatments, and ADRs was collected from the ADR notifications and from patient electronic medical records. The dependent variable was the mentioning of ADRs in the discharge reports, while characteristics of the ADRs, pharmacovigilance causality algorithms, and some of the suspected drugs themselves were the independent variables during bivariant analysis. A total of 286 reports of suspected ADRs from 271 patients (50.2% female; 77% adults) were included. Information regarding the ADRs was present in the discharge reports for 238 reports (83.2%); the ADR seriousness and the lack of potential alternative causes were the only associated factors. Withdrawal or withdrawal and substitution by an alternative drug were the most common therapeutic decisions, although often no recommendation was made. Overall, there is still room for improvement in terms of including information related to ADRs in hospital discharge reports.

Withdrawal of hospital outpatient treatments in severe diseases due to unacceptable toxicity: A retrospective study from the register of patients and treatments.

AIM: To retrospectively analyse hospital outpatient treatment (HOT) withdrawal due to unacceptable toxicity at our hospital. Information regarding unacceptable toxicity leading to treatment withdrawal was recorded. METHODS: HOT interruptions because of unacceptable toxicity were identified from the Register of Patients and Treatments (RPT) (January 2014 to December 2017). Information regarding the demographic and clinical characteristics of patients, adverse drug reactions (ADRs) and drug treatments was retrieved from electronic health records. Causality and previous knowledge of ADRs were assessed according to the Spanish Pharmacovigilance System algorithm. Information regarding HOT risk management plans (RMPs) and their classification as inverted black triangle medicines was obtained from the European Medicines Agency (EMA). RESULTS: HOTs were withdrawn due to unacceptable toxicity in 136 (1.5%) registries corresponding to 135 (1.7%) patients. Fifty-one different HOTs (38.6% of those registered) were involved in 240 ADR/HOT pairs: 24 (47%) were additional monitoring medicines and 37 (72.5%) were EMA RMPs. The most frequent medicines involved in ADRs were lenalidomide (30, 12.5%) (mainly neutropenia, thrombocytopenia and bicytopenia), bevacizumab (19, 7.9%) (mainly venous and pulmonary thromboembolism) and sunitinib (13, 5.4%) (mainly thromboembolic events, diarrhoea and worsening of chronic renal failure). Cytopenia (40, 17.3%), diarrhoea (15, 6.5%), asthenia (9, 3.9%) and neuropathy (6, 2.6%) were the most frequent ADRs. All ADRs were severe, 10 (6 patients) had been poorly described or were unknown and only 9 (5 patients) had been reported by spontaneous notification. CONCLUSIONS: Valuable information regarding severe and unknown ADRs was obtained from the RPT. Such registers are useful tools to complement spontaneous ADR notifications.

A case series of confusional states and other neurotoxic effects caused by ertapenem.

Ten cases of ertapenem neurotoxicity, mainly confusional states, are described, some of them with fatal outcomes. The majority of patients (90%) had a creatinine clearance (CrCl) < 50 mL/min/1.73m2 at some point during treatment and hypoalbuminaemia was always present when ertapenem treatment was started. The pharmacokinetic and pharmacodynamic properties of this carbapenem could favour a different profile, and approved doses can be excessive in some patients with moderate renal failure (CrCl 31-59 mL/min/1.73 m2 ). It may be necessary to re-evaluate renal function during treatment and adjust doses or reconsider the adequacy of treatment based on clinical judgement, especially if relevant changes in the CrCl occur (i.e. a reduction to ≤30 mL/min/1.73 m2 ) or unexplained behavioural disorders are detected. The onset of the symptoms of ertapenem neurotoxicity can be insidious and go unnoticed, and so a knowledge and early suspicion of confusional states are important to improve the patient prognosis.

Paracetamol in therapeutic dosages and acute liver injury: causality assessment in a prospective case series.

BACKGROUND: Acute liver injury (ALI) induced by paracetamol overdose is a well known cause of emergency hospital admission and death. However, there is debate regarding the risk of ALI after therapeutic dosages of the drug.The aim is to describe the characteristics of patients admitted to hospital with jaundice who had previous exposure to therapeutic doses of paracetamol. An assessment of the causality role of paracetamol was performed in each case. METHODS: Based on the evaluation of prospectively gathered cases of ALI with detailed clinical information, thirty-two cases of ALI in non-alcoholic patients exposed to therapeutic doses of paracetamol were identified. Two authors assessed all drug exposures by using the CIOMS/RUCAM scale. Each case was classified into one of five categories based on the causality score for paracetamol. RESULTS: In four cases the role of paracetamol was judged to be unrelated, in two unlikely, and these were excluded from evaluation. In seven of the remaining 26 cases, the RUCAM score associated with paracetamol was higher than that associated with other concomitant medications. The estimated incidence of ALI related to the use of paracetamol in therapeutic dosages was 0.4 per million inhabitants older than 15 years of age and per year (99%CI, 0.2-0.8) and of 10 per million paracetamol users-year (95% CI 4.3-19.4). CONCLUSIONS: Our results indicate that paracetamol in therapeutic dosages may be considered in the causality assessment in non-alcoholic patients with liver injury, even if the estimated incidence of ALI related to paracetamol appears to be low.

Preliminary efficacy and safety of an oromucosal standardized cannabis extract in chemotherapy-induced nausea and vomiting.

AIMS: Despite progress in anti-emetic treatment, many patients still suffer from chemotherapy-induced nausea and vomiting (CINV). This is a pilot, randomized, double-blind, placebo-controlled phase II clinical trial designed to evaluate the tolerability, preliminary efficacy, and pharmacokinetics of an acute dose titration of a whole-plant cannabis-based medicine (CBM) containing delta-9-tetrahydrocannabinol and cannabidiol, taken in conjunction with standard therapies in the control of CINV. METHODS: Patients suffering from CINV despite prophylaxis with standard anti-emetic treatment were randomized to CBM or placebo, during the 120 h post-chemotherapy period, added to standard anti-emetic treatment. Tolerability was measured as the number of withdrawals from the study during the titration period because of adverse events (AEs). The endpoint for the preliminary efficacy analysis was the proportion of patients showing complete or partial response. RESULTS: Seven patients were randomized to CBM and nine to placebo. Only one patient in the CBM arm was withdrawn due to AEs. A higher proportion of patients in the CBM group experienced a complete response during the overall observation period [5/7 (71.4%) with CMB vs. 2/9 (22.2%) with placebo, the difference being 49.2% (95% CI 1%, 75%)], due to the delayed period. The incidence of AEs was higher in the CBM group (86% vs. 67%). No serious AEs were reported. The mean daily dose was 4.8 sprays in both groups. CONCLUSION: Compared with placebo, CBM added to standard antiemetic therapy was well tolerated and provided better protection against delayed CINV. These results should be confirmed in a phase III clinical trial.

Consent in clinical trials: what do patients know?

OBJECTIVE: To assess participants' knowledge of key aspects about the clinical trials in which they are enrolled, describe the consent process, and assess the importance that investigators give to various aspects of trial information when verbally informing candidates. DESIGN: Prospective study based on a structured questionnaire interview of participants within 3 months after trial enrollment and an anonymous questionnaire sent to clinical trial investigators. SUBJECTS: A total of 140 participants included in 40 clinical trials were interviewed, and 51 investigators answered the questionnaire. RESULTS: The formal steps to obtain informed consent were usually carried out. Participants were aware of the purpose of the trial and the right to discontinue participation, but only 23% knew that treatment was randomly allocated, 57% knew they might receive a placebo, and 42% was aware that adverse effects could occur. Patients who had read the information sheet had better knowledge of most aspects, except for the risk of adverse effects. The investigators considered that compensation, insurance coverage, possibility of receiving a placebo, and treatment allocation were the least important aspects of the trial when informing candidates for participation. CONCLUSIONS: Although the formal steps for obtaining informed consent were usually carried out, a relevant percentage of patients included in clinical trials were unaware of important aspects of their participation. Patients showed more limited knowledge about the same points that investigators considered less important when informing potential participants. Deferring signature on the consent form and encouraging reading of the information sheet may improve participants' knowledge about clinical trials.

Randomized clinical trial of the effectiveness of a home-based intervention in patients with heart failure: the IC-DOM study.

INTRODUCTION AND OBJECTIVES: The objective of this study was to determine whether a home-based intervention can reduce mortality and hospital readmissions and improve quality of life in patients with heart failure. METHODS: A randomized clinical trial was carried out between January 2004 and October 2006. In total, 283 patients admitted to hospital with a diagnosis of heart failure were randomly allocated to a home-based intervention (intervention group) or usual care (control group). The primary end-point was the combination of all-cause mortality and hospital readmission for worsening heart failure at 1-year follow-up. RESULTS: The primary end-point was observed in 41.7% of patients in the intervention group and in 54.3% in the control group. The hazard ratio was 0.70 (95% confidence interval [CI] 0.55-0.99). Taking significant clinical variables into account slightly reduced the hazard ratio to 0.62 (95% CI 0.50-0.87). At the end of the study, the quality of life of patients in the intervention group was better than in the control group (18.57 vs. 31.11; P< .001). CONCLUSIONS: A home-based intervention for patients with heart failure reduced the aggregate of mortality and hospital readmissions and improved quality of life.

Ensayo clínico aleatorizado para evaluar la efectividad de una intervención domiciliaria en pacientes con insuficiencia cardiaca: estudio IC-DOM / Randomized clinical trial of the effectiveness of a home-based intervention in patients with heart failure: the IC-DOM Study l408

Introducción y objetivos. El objetivo de este estudio es evaluar si una intervención domiciliaria reduce la mortalidad y los reingresos hospitalarios de pacientes con insuficiencia cardiaca y mejora su calidad de vida. Métodos. Ensayo clínico aleatorizado, realizado desde enero de 2004 a octubre de 2006. Se aleatorizó a 283 pacientes, diagnosticados de insuficiencia cardiaca e ingresados en el hospital, al grupo de atención domiciliaria (grupo intervención) o al grupo de atención habitual (grupo control). La variable principal de resultado se midió al año de seguimiento y fue la combinación de la mortalidad por todas las causas y los reingresos hospitalarios debido al empeoramiento de la insuficiencia cardiaca. Resultados. La variable principal se observó en el 41,7% de los pacientes del grupo intervención y en el 54,3% del grupo control. La razón de riesgos (HR) fue 0,70 (intervalo de confianza [IC] del 95%, 0,55-0,99). Incluyendo variables clínicas relevantes, la razón de riesgos disminuyó ligeramente (HR = 0,62; IC del 95%, 0,50-0,87). Al final del estudio, los pacientes del grupo intervención tenían una mejor calidad de vida que los pacientes del grupo control (18,57 frente a 31,11; p < 0,001). Conclusiones. Una intervención basada en la atención domiciliaria en pacientes con insuficiencia cardiaca reduce el conjunto de mortalidad y reingresos hospitalarios y mejora la calidad de vida (AU)

Introduction and objectives. The objective of this study was to determine whether a home-based intervention can reduce mortality and hospital readmissions and improve quality of life in patients with heart failure. Methods. A randomized clinical trial was carried out between January 2004 and October 2006. In total, 283 patients admitted to hospital with a diagnosis of heart failure were randomly allocated to a home-based intervention (intervention group) or usual care (control group). The primary end-point was the combination of all-cause mortality and hospital readmission for worsening heart failure at 1-year follow-up. Results. The primary end-point was observed in 41.7% of patients in the intervention group and in 54.3% in the control group. The hazard ratio was 0.70 (95% confidence interval [CI], 0.55-0.99). Taking significant clinical variables into account slightly reduced the hazard ratio to 0.62 (95% CI, 0.50-0.87). At the end of the study, the quality of life of patients in the intervention group was better than in the control group (18.57 vs 31.11; P < .001). Conclusions. A home-based intervention for patients with heart failure reduced the aggregate of mortality and hospital readmissions and improved quality of life (AU)

Prospective surveillance of acute serious liver disease unrelated to infectious, obstructive, or metabolic diseases: epidemiological and clinical features, and exposure to drugs.

BACKGROUND/AIMS: Acute serious liver disease which is unrelated to infectious, obstructive, or metabolic disease is uncommon. Many drugs have been implicated. Data on its epidemiology are scarce. We performed a population-based prospective study of acute serious liver disease in Catalonia (Spain). METHODS: A collaborating hospital network was set up. All patients with acute serious liver disease and negative viral hepatitis serological markers, without an obvious cause of liver disease, were included. RESULTS: The incidence of acute serious liver disease was 7.4 per 10(6) inhabitants per year (95% CI; 6.0-8.8), which increased with age. The incidence of hepatocellular acute serious liver disease (3.84 per 10(6) per year) was greater than that of cholestatic and mixed patterns. The case-fatality ratio was 11.9% and mortality 0.8 per million person-years. The risk of death was similar among patients with hepatocellular and cholestatic patterns. Non-steroidal antiinflammatory drugs, analgesics, and antibacterials were the most frequently used drugs. CONCLUSIONS: Acute serious liver disease which is unrelated to infectious, obstructive, or metabolic disease is rare. Its incidence increases with age. The prognosis of cholestatic acute serious liver disease does not significantly differ from that of the hepatocellular pattern. Non-steroidal antiinflammatory drugs, analgesics, and antibacterials were the most common drugs likely to be responsible for acute liver disease.