Description of the Protocols for Randomized Controlled Trials on Cancer Drugs Conducted in Spain (1999-2003)

To describe the characteristics of randomized controlled clinical trials (RCT) on cancer drugs conducted in Spain between 1999 and 2003 based on their protocols. We conducted an observational retrospective cohort study to identify the protocols of RCTs on cancer drugs authorized by the Agencia Española del Medicamento y Productos Sanitarios (AEMPS) (Spanish Agency for Medicines and Medical Devices) during 1999-2003. A descriptive analysis was completed and the association between variables based on the study setting and sponsorship were assessed. We identified a total of 303 protocols, which included 176,835 potentially eligible patients. Three-quarter of the studies were internationally-based, 61.7% were phase III, and 76.2% were sponsored by pharmaceutical companies. The most frequently assessed outcomes were response rate (24.7%), overall survival (20.7%), and progression-free survival (14.5%). Of all protocols, 10.6% intended to include more than 1000 patients (mean: 2442, SD: 2724). Compared with their national counterparts, internationally-based studies were significantly larger (p<0.001) and were more likely to implement centralized randomization (p<0.001), blinding of the intervention (p<0.001), and survival as primary outcome (p<0.001). Additionally, most internationally-based studies were sponsored by pharmaceutical companies (p<0.01). In a high percentage of protocols, the available information was not explicit enough to assess the validity of each trial. Compared to other European countries, the proportion of Spanish cancer drugs protocols registered at (7%) was lower. RCTs on cancer drugs conducted in Spain between 1999 and 2003 were more likely to be promoted by pharmaceutical companies rather than by non-profit national groups. The former were more often part of international studies, which generally had better methodological quality than national ones. There are some worldwide on-going initiatives that aim to increase the transparency and quality of future research

Spontaneous reporting of adverse drug reactions in a pediatric population in a tertiary hospital

The pediatric population is a vulnerable group for adverse drug reactions (ADRs), and data on spontaneous reporting of ADRs in the hospital setting are scarce. We conducted a retrospective analysis of ADRs in pediatric patients spontaneously reported by health care professionals to a Pharmacovigilance Program in a tertiary hospital between 2010 and 2020, and we compared characteristics of ADRs between pediatric age subgroups. From 1787 spontaneously reported ADRs in an 11-year period, 103 (5.85%) were pediatric ADRs. The median age of patients with ADRs was 8.4 years (range 1 day-17 years) and 57.3% were male. The most frequent ADRs reported were nervous system disorders (13.6%) and the most frequently involved drugs were antineoplastics and immunodulators (32.4%). A 59.2% of the ADRs were serious and 55.3% were classified as being type B reactions. Medication errors were involved in 7.8% of the ADRs and 11.9% of the suspected drugs were used off-label. Spontaneous reports of ADRs in newborns, infants, and toddlers were more serious and less often described in the product data sheet than in children and adolescents (p < 0.001 and p = 0.004 respectively). Medication errors were more frequent in patients under two years of age. These results should be interpreted with caution due to under-reporting and biases in spontaneous reporting of ADRs

Randomized Double-Blind Multicentre Clinical Trial Comparing the Efficacy of Calcium dobesilate with placebo in the treatment of Chronic Venous Disease

Producción CientíficaObjective. To assess the efficacy of calcium dobesilate on the quality-of-life (QoL) of patients with chronic venous disease (CVD). Design. Randomised, parallel, double blind, placebo-controlled clinical trial. Methods. Patients were recruited from vascular surgery clinics and randomised to 500 mg capsules of calcium dobesilate twice a day for 3 months or placebo. The primary outcome measure was ‘QoL after 3 months’ treatment measured by the specific Chronic Insufficiency Venous International Questionnaire (CIVIQ). Secondary outcomes were QoL at 12 months and assessment of the CVD signs and symptoms. The principal analysis was undertaken on the intention-to-treat (ITT) data. Results. Five hundred and nine patients were recruited (246 to calcium dobesilate and 263 to placebo). The analysis of the ‘QoL after 3 months’ showed no significant differences between groups ( p ¼ 0.07). For secondary outcomes, oedema and symptoms of CVD, there were no significant differences between groups. In a multi-factorial analysis, the ‘QoL at 12 months’ was better in the calcium dobesilate group than in placebo group ( p ¼ 0.02). Conclusions. Treatment with calcium dobesilate was not found to be superior to placebo on the QoL of CVD patients. The sustained effect of calcium dobesilate observed after treatment should be confirmed in future studies. 2007 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved

Indoor falls and number of previous falls are independent risk factors for long-term mortality after a hip fracture

Hip fractures are almost always the result of a fall. Causes and circumstances of falls may differ between frail and vigorous patients. To describe the circumstances of falls causing hip fractures, number of falls during the previous year, and their association with long-term mortality. The study is a retrospective review conducted in a tertiary university hospital serving a population of 425,000 inhabitants in Barcelona. All patients admitted with hip fractures with medical records describing the circumstances and number of previous falls were included. The number of falls in the previous 12 months was recorded, including the one causing the fracture. The circumstances of the index fall were dichotomized according to whether it was from the patient's own height or above; day or night; indoors or outdoors, due to intrinsic or extrinsic causes. Cumulative mortality was recorded for almost 5 years after hip fracture. Indoor falls were strongly associated with shorter survival. Falling more than once in the previous year was also a risk factor for long-term mortality (hazard ratio 1.461, p < 0.001 and hazard ratio 1.035, p = 0.008 respectively). Indoor falls and falling more than once in the previous year are long-term risk factors for mortality after hip fractures. It is always essential to take a careful patient history on admission to determine the number of falls and their circumstances, and special care should be taken to reduce mortality in patients at high risk

Alzheimer’s Disease Dementia Guidelines for Diagnostic Testing: A Systematic Review

Alzheimer’s disease dementia (AD dementia) is one of the most common neurodegenerative diseases worldwide, with a growing incidence during the last decades. Clinical diagnosis of cognitive impairment and presence of AD biomarkers have become important issues for early and adequate treatment. We performed a systematic literature search and quality appraisal of AD dementia guidelines, published between 2005 and 2011, which contained diagnostic recommendations on AD dementia. We also analyzed diagnostic recommendations related to the use of brief cognitive tests, neuropsychological evaluation, and AD biomarkers. Of the 537 retrieved references, 15 met the selection criteria. We found that Appraisal of Guidelines Research and Evaluation (AGREE)-II domains such as applicability and editorial independence had the lowest scores. The wide variability on assessment of quality of evidence and strength of recommendations were the main concerns identified regarding diagnostic testing. Although the appropriate methodology for clinical practice guideline development is well known, the quality of diagnostic AD dementia guidelines can be significantly improved

Variation in the choice of elective surgical procedure for abdominal aortic aneurysm in Spain

Abdominal aortic aneurysm; Endovascular aneurysm repair; Open surgical repairAneurisma aòrtic abdominal; Reparació endovascular d'aneurismes; Reparació quirúrgica obertaAneurisma aórtico abdominal; Reparación endovascular de aneurismas; Reparación quirúrgica abiertaOBJECTIVE: The two main surgical treatments for abdominal aortic aneurysm (AAA) are open surgical repair (OSR) and endovascular aneurysm repair (EVAR). The aim of this study was to analyze variation among Spanish hospitals in the use of OSR or EVAR for AAA. A secondary aim was to assess changes in preferences for these two procedures over time. METHODS: This was a retrospective longitudinal study based on discharge data from public hospitals in Spain during 2002-2012. Patient inclusion criteria were: age >18 years, elective admission, primary diagnosis of unruptured AAA, and surgical treatment with OSR or EVAR. The characteristics of the treating center, patients, and in-hospital mortality were recorded. RESULTS: We included 16,737 patients from 114 hospitals; 6,809 (40.7%) underwent EVAR and 9,928 (59.3%) underwent OSR. The total volume of surgeries increased throughout the period, and the probability that any given procedure was EVAR increased by 20% per year (OR 1.20, P<0.001). The volume and distribution of the two procedures varied highly across the participating hospitals. Overall, in-hospital mortality rate was 3.6% and it decreased during the study period (5.3% in 2002 and 3.2% in 2012), mainly due to a decrease in OSR-related mortality, despite a slight increase in EVAR-related mortality. Hospitals with higher surgical volumes were more likely to use EVAR and have lower in-hospital mortality rates. CONCLUSION: This study reveals high variability in the surgical treatment of unruptured AAA across Spanish hospitals. The number of interventions has increased in recent years, with EVAR accounting for a growing percentage of these surgical procedures. Overall in-hospital mortality rates decreased significantly during this period, mainly due to lower mortality among patients undergoing OSR. In-hospital mortality rates were lower in higher-volume centers, regardless of the surgical approach used. Further research on variability and appropriateness of surgical management of AAA is required to assess the suitability of concentrating elective AAA repair in more experienced centers to potentially achieve better outcomes

Safety and pharmacokinetic profile of fixed-dose ivermectin with an innovative 18mg tablet in healthy adult volunteers

Ivermectin is a pivotal drug for the control of onchocerciasis and lymphatic filariasis, which is increasingly identified as a useful drug for the control of other Neglected Tropical Diseases. Its role in the treatment of soil transmitted helminthiasis through improved efficacy against Trichuris trichiura in combination with other anthelmintics might accelerate the progress towards breaking transmission. Ivermectin is a derivative of Avermectin B1, and consists of an 80:20 mixture of the equipotent homologous 22,23 dehydro B1a and B1b. Pharmacokinetic characteristics and safety profile of ivermectin allow to explore innovative uses to further expand its utilization through mass drug administration campaigns to improve coverage rates. We conducted a phase I clinical trial with 54 healthy adult volunteers who sequentially received 2 experimental treatments using a new 18 mg ivermectin tablet in a fixed-dose strategy of 18 and 36 mg single dose regimens, compared to the standard, weight based 150-200 μg/kg, regimen. Volunteers were recruited in 3 groups based on body weight. Plasma concentrations of ivermectin were measured through HPLC up to 168 hours post treatment. Safety data showed no significant differences between groups and no serious adverse events: headache was the most frequent adverse event in all treatment groups, none of them severe. Pharmacokinetic parameters showed a half-life between 81 and 91 h in the different treatment groups. When comparing the systemic bioavailability (AUC0t and Cmax) of the reference product (WA-ref) with the other two study groups using fixed doses, we observed an overall increase in AUC0t and Cmax for the two experimental treatments of 18 mg and 36 mg. Body mass index (BMI) and weight were associated with t1/2 and V/F, probably reflecting the high liposolubility of IVM with longer retention times proportional to the presence of more adipose tissue. Systemic exposure to ivermectin (AUC0t or Cmax) was not associated with BMI or weight in our study. These findings contribute to further understand the pharmacokinetic characteristics of ivermectin, highlighting its safety across different dosing regimens. They also correlate with known pharmacokinetic parameters showing stable levels of AUC and Cmax across a wide range of body weights, which justifies the strategy of fix dosing from a pharmacokinetic perspective

Aerobic Capacity in Adults with Congenital Heart Disease: More than VO2peak, a Follow-Up Study

Adults; Aerobic capacity; Congenital heart diseaseAdultos; Capacidad aeróbica; Cardiopatía congénitaAdults; Capacitat aeròbica; Cardiopatia congènitaTo control the development of people with congenital heart disease (CHD), it is important to follow their aerobic capacity (AC), especially when they exercise. This research aimed to study the progress of AC during a follow-up of adults with CHD. This is a longitudinal study which involved 127 adults with a mean age of 33.8 (11.1) years (57.5% female; 75 moderate CHD and 52 complex CHD) who had undergone two cardiopulmonary exercise tests (CEPT) in at least one year between the first and the second test. The AC and exercise performance (EP) (duration of exercise time, velocity and percentage of grade) were assessed using a ramp protocol over a treadmill. In a mean of 4.5 (2.0) years of follow-up, there was a significant decrease in AC. The VO2peak at baseline was 27.8 (27.7) mL/kg/min (82.9% (20.3%) predicted) versus 26.6 (7.8) mL/kg/min (79.3% (20.8%) predicted) at the end of follow-up. This decline was independent of the body weight increase. There was no significant difference in HRpeak and EP among periods. These results suggest a sign of favorable evolution of adults with CHD. More research is needed to study different factors that could contribute to AC reduction.This research was funded by SUR of DEC Generalitat de Catalunya and European Union, PhD grant number 2020FI_B2_00128. The funder had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript

Patient self-management of oral anticoagulation with vitamin K antagonists in everyday practice : Clinical outcomes in a single centre cohort after long-term follow-up

Patient self-management (PSM) of vitamin K antagonists (VKA) seems a very promising model of care for oral anticoagulation in terms of efficacy and safety. In comparison with other management models of VKA therapy, the number of scientific publications supporting the advantages of PSM is more limited. Currently, most of the scarce information comes from randomized clinical trials. Moreover, a small number of studies have assessed PSM of VKA therapy in real life conditions. We analyzed clinical outcomes of 927 patients in a single center (6018.6 patient-years of follow-up). Recruitment took place between 2002 and 2017. All patients followed a structured training program, conducted by specialized nurses. Fifty percent of individuals had a mechanical heart valve (MHV), 23% suffered from recurrent venous thromboembolism (VTE) or high-risk thrombophilia, and 13% received VKA therapy because of atrial fibrillation (AF). Median follow-up was 6.5 years (range 0.1-15.97 years), median age was 58.1 years (IQR 48-65.9) and 46.5% were women. The incidence of major complications (either hemorrhagic or thromboembolic) was 1.87% patient-years (pt-ys) with a 95% CI of 1.54-2.27. The incidence of major thromboembolic events was 0.86% pt-ys (95% CI 0.64-1.13) and that of major hemorrhagic events was 1.01% pt-ys (95% CI 0.77-1.31). The incidence of intracranial bleeding was 0.22% pt-ys (95% CI 0.12-0.38). In terms of clinical indication for VKA therapy, the incidence of total major complications was 2.4% pt-ys, 2.0% pt-ys, 0.9% pt-ys and 1.34% pt-ys for MHV, AF, VTE and other (including valvulopathies and myocardiopathies), respectively. Clinical outcomes were worse in patients with multiple comorbidities, previous major complications during conventional VKA therapy, and in older individuals. The percentage of time in therapeutic range (TTR) was available in 861 (93%) patients. Overall, the mean (SD) of TTR was 63.6 ± 13.4%, being higher in men (66.2 ± 13.1%) than women (60.6 ± 13.2%), p < 0.05. In terms of clinically relevant outcomes (incidence of major complications and mortality), PSM in real life setting seems to be a very good alternative in properly trained patients

Prevalence study of intermittent hormonal therapy of Prostate Cancer patients in Spain

Background: Although intermittent androgen deprivation therapy was introduced many years ago to improve patients' quality of life with the same carcinologic efficiency as continuous hormonal therapy, recent data suggest that intermittency could be underutilised. This study aims to estimate the prevalence of prostate cancer patients receiving intermittent androgen deprivation therapy in Spain. Methods: A retrospective, longitudinal study was conducted using electronic drug dispensation data from four Spanish autonomous communities, which encompass 17.23 million inhabitants (36.22% of the total population in Spain). We estimated intermittent androgen therapy use (%IAD) and the prevalence of patients under intermittent androgen therapy in reference to the total number of PC patients using hormonal therapy (P IAD) and stratified by region. Other outcome variables included the pharmaceutical forms dispensed and the total direct annual expenditure on androgen deprivation therapy-associated medications. Results: A total of 863,005 dispensations corresponding to a total of 65,752 men were identified, treated with either luteinizing hormone-releasing hormone (LHRH) analogues (353,162) administered alone or in combination with anti-androgens (509,843). Overall, the mean (±SD) age of the patients was 76.9 (±10.4) years. Results revealed that the mean annual P IAD along the study was 6.6% in the total population studied, and the overall %IAD during the five-year study period was 5.6%. The mean cost of hormonal therapy per year was 25 million euros for LHRH analogues and 6.3 million euros for anti-androgens. Conclusions: Few prostate cancer patients in Spain use the intermittent androgen deprivation therapy suggesting underutilization of a perfectly valid option for a significant proportion of patients, missing the opportunity to improve their quality of life and to reduce costs for the National Health Service with comparable overall survival rates than continuous therapy.</p