Documento de expertos sobre el uso apropiado de los SYSADOA en situaciones clínicas controvertidas / Experts Document About an Adequate Utilization of SYSADOAs in Controversial Clinical Situations

Antecedentes y objetivo: Los SYSADOA (del inglés, symptomatic slow-acting drugs for osteoarthritis) orales son compuestos naturales que han demostrado ser útiles y seguros en el tratamiento de la artrosis (AO). Sin embargo, su uso en ciertas situaciones clínicas carece aún de evidencia científica y recomendaciones claras. El objetivo de este trabajo fue conocer la opinión de un grupo de expertos sobre el uso de los SYSADOA en el tratamiento de la AO en situaciones clínicas controvertidas. Materiales y métodos: Siguiendo el método del uso apropiado mediante la técnica Delphi, se valoraron 206 consultas concretas, estructuradas en 24 preguntas clínicas. Un panel de expertos, compuesto por un total de 15 especialistas, respondió a las dos rondas de consulta a través de una plataforma online. Los resultados se analizaron y debatieron en una reunión presencial con los coordinadores y el comité científico. Según el porcentaje de panelistas que coincidieron en los mismos, se clasificaron los resultados en términos de unanimidad, consenso, mayoría y discrepancia. Resultados: Se consensuaron los siguientes puntos: (1) el fenotipo del paciente condiciona el uso de los SYSADOA orales; (2) los SYSADOA orales se consideran adecuados en la AO primaria (rodilla, mano y cadera) y en algunos tipos de AO secundaria; no se consideran adecuados en AO erosiva de manos, hombro, columna y tobillo; (3) los SYSADOA orales pueden ser prescritos a pacientes con riesgo o enfermedad cardiovascular, enfermedad digestiva, hipertensión, dislipemia, enfermedad vascular periférica, diabetes tipo 2 y, a excepción de diacereína, en pacientes con reflujo esofágico. No se obtuvo acuerdo en la prescripción de los SYSADOA orales en pacientes con enfermedad hepática y renal.(AU)

Background and objective: SYSADOAs (symptomatic slow-acting drugs for osteoarthritis) are natural compounds that have been shown to be useful and safe in the treatment of osteoarthritis (OA). However, their use in certain clinical situations still lacks scientific evidence and clear recommendations. The objective of this work was to learn the opinion of a group of experts regarding the appropriate use of SYSADOA in the treatment of OA in controversial clinical situations. Materials and methods: Following the Delphi technique, 206 specific consultations, structured in 24 clinical questions, were evaluated. A panel of experts composed of a total of 15 specialists, answered the two rounds of consultation through an online platform. The results were analysed and discussed in a face-to-face meeting with the coordinators and the scientific committee. According to the percentage of panellists who agreed on their findings, the results were classified in terms of unanimity, consensus, majority and discrepancy. Results: The following points were agreed upon: (1) the patient's phenotype determines the use of SYSADOAs; (2) SYSADOAs are considered appropriate in primary OA (knee, hand and hip) and in some types of secondary OA; they are not considered appropriate in OA of the shoulder, spine, ankle and erosive OA of the hands; (3) SYSADOAs may be prescribed for patients at risk of or with cardiovascular disease, digestive disease, hypertension, dyslipaemia, peripheral vascular disease, type 2 diabetes and, excluding diacerein, for patients with oesophageal reflux. No agreement was obtained on the prescription of SYSADOAs for patients with hepatic and renal disease. Conclusions: There is limited literature on the use of SYSADOAs for the treatment of OA in controversial situations. Through this work it has been possible to establish the position of a group of experts regarding clinical situations for which there is no scientific evidence concerning their use.(AU)

Experts document about an adequate utilization of SYSADOAs in controversial clinical situations.

BACKGROUND AND OBJECTIVE: SYSADOAs (Symptomatic Slow-Acting Drugs for Osteoarthritis) are natural compounds that have been shown to be useful and safe in the treatment of osteoarthritis (OA). However, their use in certain clinical situations still lacks scientific evidence and clear recommendations. The objective of this work was to learn the opinion of a group of experts regarding the appropriate use of SYSADOA in the treatment of OA in controversial clinical situations. MATERIALS AND METHODS: Following the Delphi technique, 206 specific consultations, structured in 24 clinical questions, were evaluated. A panel of experts composed of a total of 15 specialists, answered the two rounds of consultation through an online platform. The results were analysed and discussed in a face-to-face meeting with the coordinators and the scientific committee. According to the percentage of panellists who agreed on their findings, the results were classified in terms of unanimity, consensus, majority and discrepancy. RESULTS: The following points were agreed upon: (1) the patient's phenotype determines the use of SYSADOAs; (2) SYSADOAs are considered appropriate in primary OA (knee, hand and hip) and in some types of secondary OA; they are not considered appropriate in OA of the shoulder, spine, ankle and erosive OA of the hands; (3) SYSADOAs may be prescribed for patients at risk of or with cardiovascular disease, digestive disease, hypertension, dyslipaemia, peripheral vascular disease, type 2 diabetes and, excluding Diacerein, for patients with oesophageal reflux. No agreement was obtained on the prescription of SYSADOAs for patients with hepatic and renal disease. CONCLUSIONS: There is limited literature on the use of SYSADOAs for the treatment of OA in controversial situations. Through this work it has been possible to establish the position of a group of experts regarding clinical situations for which there is no scientific evidence concerning their use. This work may contribute towards improving the management protocols of SYSADOAs in the treatment of OA and offer a useful approach in uncertain situations.

Pilot study of the usability and functionality of a smart ph meter and a mobile medical application for urine ph monitoring. / Estudio piloto de la usabilidad y la funcionalidad de un pH-metro inteligente y una aplicación móvil de salud para la monitorización del pH urinario.

OBJECTIVES: Portable pH meters are robust and reliable tools for measuring urinary pH bypatients at home. This study evaluated the usability of a prototype smart Lit-Control® pH Meter and an associated mobile medical app, with the aim of identifying possible design and functionality issues along with usability problems among non-expert voluntary users. MATHERIALS AND METHODS: Twenty-one individuals of both genders, between 26 and 61 years old, tested the dyad pH meter/app for 14 days (three readings per day). The participants were asked to carry out a sequence of use of the system equivalent to what an intended user would do for urinary pH self-monitoring. At the end of the trial period, each participant filled out study questionnaires regarding the learning times, i.e. the time used by a new user to perform a task with the technology, usability, errors detected, and suggestions for improvement. RESULTS: The mean age of participants was 35.4 (range, 26 to 61) years. The readings from the pH meter yielded average values of 5.72 (SD = 0.26), 6.13 (SD= 0.43), and 5.47 (SD = 1.27) for the morning, evening, and night micturitions, respectively. The time of the day with greater adherence was the morning (49.7% of all readings). The learning times were in general short as reported by the participants: 73.7% were able to register in the App, rated as the least easy task, in less than two and a half minutes. The task of uploading the pH readings, both manually and automatically, was mostly performed in less than 35 seconds. CONCLUSION: This pilot study of real-world usage pattern shows that the dyad smart Lit-Control pH meter/Appwas perceived as fit for purpose by non-expert volunteers and had no relevant functionality or usability issues that would pose a significant barrier to the intended users. New studies are ongoing in order to test the usability by patients with lithiasis history.

OBJETIVOS: Los medidores de pH (pH-metros) portátiles son herramientas precisas y fiables para determinar el pH urinario de los pacientes en su domicilio. Este estudio evaluó la usabilidad de un prototipo de pH-metro inteligente Lit-Control® y una aplicación móvil asociada (App), con el objetivo de identificar posibles problemas de diseño y funcionalidad, así como su usabilidad, entre participantes voluntarios no expertos.MATERIALES Y MÉTODOS: Veintiún individuos de ambos sexos, entre 26 y 61 años, probaron la combinación pH-metro/aplicación durante 14 días (tres lecturas al día). Se pidió a los participantes que efectuaran una secuencia de uso del sistema equivalente a lo que haría un supuesto usuario para la auto-monitorización del pH urinario. Al final del período de prueba, cada participante rellenó los cuestionarios del estudio sobre los tiempos de aprendizaje, es decir, el tiempo empleado para realizar cada tarea con la nueva tecnología, su usabilidad, los errores detectados y sugerencias de mejora. RESULTADOS: La edad media de los participantes fue 35,4 (rango, 26 a 61) años. Las lecturas con el pH-metro obtuvieron un valor promedio de 5,72 (DE = 0,26), 6,13 (DE = 0,43) y 5,47 (DE = 1,27) para la orina de la mañana, tarde y noche, respectivamente. El momento del día con mayor adherencia fue la mañana (49,7% de todas las lecturas). Los tiempos de aprendizaje fueron en general cortos según lo informado por los participantes: el 73,7% pudo registrarse en la App,calificada como la tarea menos fácil, en menos de dos minutos y medio. La tarea de descargar las mediciones del pH, tanto manual como automáticamente, se realizó generalmente en menos de 35 segundos.CONCLUSIÓN: Este estudio piloto sobre el patrón de uso en el mundo real muestra que la combinación del pH-metro inteligente Lit-Control y su aplicación móvil se percibió como adecuada para su propósito por voluntarios no expertos y no tuvo problemas de funcionalidad o usabilidad relevantes que pudieran representar una barrera significativa para los futuros usuarios. Se están realizando nuevos estudios para evaluar la usabilidad en pacientes con antecedentes de litiasis.

Pilot study of the usability and functionality of a smart pH meter and a mobile medical application for urine pH monitoring / Estudio piloto de la usabilidad y la funcionalidad de un pH-metro inteligente y una aplicación móvil de salud para la monitorización del pH urinario

Objetives: Portable pH meters are robust and reliable tools for measuring urinary pH bypatients at home. This study evaluated the usability of a prototype smart Lit-Control® pH Meterand an associated mobile medical app, with the aim of identifying possible design andfunctionality issues along with usability problems among non-expert voluntary users.Materials and methods: Twenty-one individuals of both sexes, between 25 and 65years old, tested the dyad pH meter/app for 14 days (three readings per day). The participantswere asked to carry out a sequence of use of the system equivalent to what an intended userwould do for urinary pH self-monitoring. At the end of the trial period, each participant filled outstudy questionnaires regarding the learning times, i.e. the time used by a new user to performa task with the technology, usability, errors detected, and suggestions for improvement.Results: The mean age of participants was 35.4 (range, 26 to 61) years. The readings fromthe pH meter yielded average values of 5.72 (SD = 0.26), 6.13 (SD = 0.43), and 5.47 (SD =1.27) for the morning, evening, and night urines, respectively. The time of the day with greateradherence was the morning (49.7% of all readings). The learning times were in general shortas reported by the participants: 73.7% were able to register in the App, rated as the least easy task, in less than two and a half minutes. The task of uploading the pH readings, both manuallyand automatically, was mostly performed in less than 35 seconds.Conclusion: This pilot study of real-world usage pattern shows that the dyad smart Lit-Control pH meter/App was perceived as fit for purpose by non-expert volunteers and had norelevant functionality or usability issues that would pose a significant barrier to the intendedusers. New studies are ongoing in order to test the usability by patients with lithiasis history.(AU)

Objetivos: Los medidores de pH (pH-metros) portátiles son herramientas precisas y fiablespara determinar el pH urinario de los pacientes en su domicilio. Este estudio evaluó lausabilidad de un prototipo de pH-metro inteligente Lit-Control® y una aplicación móvilasociada (App), con el objetivo de identificar posibles problemas de diseño y funcionalidad,así como su usabilidad, entre participantes voluntarios no expertos.Material y métodos: Veintiún individuos de ambos sexos, entre 25 y 65 años,probaron la combinación pH-metro/aplicación durante 14 días (tres lecturas al día). Se pidió alos participantes que efectuaran una secuencia de uso del sistema equivalente a lo que haríaun supuesto usuario para la auto-monitorización del pH urinario. Al final del período de prueba,cada participante rellenó los cuestionarios del estudio sobre los tiempos de aprendizaje, esdecir, el tiempo empleado para realizar cada tarea con la nueva tecnología, su usabilidad, loserrores detectados y sugerencias de mejora.Resultados: La edad media de los participantes fue 35,4 (rango, 26 a 61) años. Laslecturas con el pH-metro obtuvieron un valor promedio de 5,72 (DE = 0,26), 6,13 (DE = 0,43)y 5,47 (DE = 1,27) para la orina de la mañana, tarde y noche, respectivamente. El momentodel día con mayor adherencia fue la mañana (49,7% de todas las lecturas). Los tiempos deaprendizaje fueron en general cortos según lo informado por los participantes: el 73,7% pudoregistrarse en la App, calificada como la tarea menos fácil, en menos de dos minutos y medio.La tarea de descargar las mediciones del pH, tanto manual como automáticamente, se realizógeneralmente en menos de 35 segundos.Conclusiones: Este estudio piloto sobre el patrón de uso en el mundo real muestra que lacombinación del pH-metro inteligente Lit-Control y su aplicación móvil se percibió comoadecuada para su propósito por voluntarios no expertos y no tuvo...(AU)

A patients' view of OA: the Global Osteoarthritis Patient Perception Survey (GOAPPS), a pilot study.

BACKGROUND: Globally, osteoarthritis (OA) is the third condition associated with disability. There is still poor treatment in OA but science holds the key to finding better treatments and a cure. It is essential to learn what's important to patients from them to implement the most effective OA management. The OA Patients Task Force, conducted the Global OA Patient Perception Survey (GOAPPS)-the first global survey made by patients to analize the quality of life (QoL) & patient perceptions of care. The goal was to collect data on OA patients' perception of OA to understand patients' needs and expectations to improve OA management. METHODS: Observational, cross-sectional study by online survey data collection from six countries, translated into three languages. The questionnaire was comprised of 3 sections: patient demographics and clinical symptomology characteristics; relationship with physicians: perception of attention, treatment, and information provided; and OA impact on daily activity and QoL. The results of the survey were evaluated using the Limited Data Set. The survey results were analyzed using descriptive statistics to characterize the patients' answers. Additionally, Cronbach's alpha was calculated to determine internal consistency validity. RESULTS: A total of 1512 surveys were completed in 6 countries. 84.2% of respondents reported pain/tenderness and 91.1% experienced limitations to physical activities. 42.3% of patients were not satisfied with their current OA treatment. 86% had comorbidities, especially hypertension, and obesity. 51.3 and 78% would like access to additional drug or additional non-drug/non-surgical treatments respectively. 48.2% of patients perceived their QoL to be affected by OA. The Cronbach's alpha was 0.61. CONCLUSIONS: OA has a significant impact on patients' daily activities and their desire to play an active role in managing this disease. Patients are seeking additional treatments, especially no pharmacological/no surgical treatments stressing the need for investing in clinical research, implementing OA preventive measures, and managing interventions to improve the healthcare value chain in OA.

Experts Document About an Adequate Utilization of SYSADOAs in Controversial Clinical Situations. / Documento de expertos sobre el uso apropiado de los SYSADOA en situaciones clínicas controvertidas.

BACKGROUND AND OBJECTIVE: SYSADOAs (symptomatic slow-acting drugs for osteoarthritis) are natural compounds that have been shown to be useful and safe in the treatment of osteoarthritis (OA). However, their use in certain clinical situations still lacks scientific evidence and clear recommendations. The objective of this work was to learn the opinion of a group of experts regarding the appropriate use of SYSADOA in the treatment of OA in controversial clinical situations. MATERIALS AND METHODS: Following the Delphi technique, 206 specific consultations, structured in 24 clinical questions, were evaluated. A panel of experts composed of a total of 15 specialists, answered the two rounds of consultation through an online platform. The results were analysed and discussed in a face-to-face meeting with the coordinators and the scientific committee. According to the percentage of panellists who agreed on their findings, the results were classified in terms of unanimity, consensus, majority and discrepancy. RESULTS: The following points were agreed upon: (1) the patient's phenotype determines the use of SYSADOAs; (2) SYSADOAs are considered appropriate in primary OA (knee, hand and hip) and in some types of secondary OA; they are not considered appropriate in OA of the shoulder, spine, ankle and erosive OA of the hands; (3) SYSADOAs may be prescribed for patients at risk of or with cardiovascular disease, digestive disease, hypertension, dyslipaemia, peripheral vascular disease, type 2 diabetes and, excluding diacerein, for patients with oesophageal reflux. No agreement was obtained on the prescription of SYSADOAs for patients with hepatic and renal disease. CONCLUSIONS: There is limited literature on the use of SYSADOAs for the treatment of OA in controversial situations. Through this work it has been possible to establish the position of a group of experts regarding clinical situations for which there is no scientific evidence concerning their use. This work may contribute towards improving the management protocols of SYSADOAs in the treatment of OA and offer a useful approach in uncertain situations.

Global management of patients with knee osteoarthritis begins with quality of life assessment: a systematic review.

BACKGROUND: Knee osteoarthritis (KOA) is a prevalent form of chronic joint disease associated with functional restrictions and pain. Activity limitations negatively impact social connectedness and psychological well-being, reducing the quality of life (QoL) of patients. The purpose of this review is to summarize the existing information on QoL in KOA patients and share the reported individual factors, which may influence it. METHODS: We conducted a systematic review examining the literature up to JAN/2017 available at MEDLINE, EMBASE, Cochrane, and PsycINFO using KOA and QOL related keywords. Inclusion criteria were QOL compared to at least one demographic factor (e.g., age, gender), lifestyle factor (e.g., functional independence), or comorbidity factor (e.g., diabetes, obesity) and a control group. Analytical methods were not considered as part of the original design. RESULTS: A total of 610 articles were reviewed, of which 62 met inclusion criteria. Instruments used to measure QoL included: SF-36, EQ-5D, KOOS, WHOQOL, HAS, AIMS, NHP and JKOM. All studies reported worse QoL in KOA patients when compared to a control group. When females were compared to males, females reported worse QOL. Obesity as well as lower level of physical activity were reported with lower QoL scores. Knee self-management programs delivered by healthcare professionals improved QoL in patients with KOA. Educational level and higher total mindfulness were reported to improve QoL whereas poverty, psychological distress, depression and lacking familial relationships reduce it. Surgical KOA interventions resulted in good to excellent outcomes generally; although, results varied by age, weight, and depression. CONCLUSION: KOA has a substantial impact on QoL. In KOA patients, QoL is also influenced by specific individual factors including gender, body weight, physical activity, mental health, and education. Importantly, education and management programs designed to support KOA patients report improved QoL. QoL data is a valuable tool providing health care professionals with a better comprehension of KOA disease to aid implementation of the most effective management plan.

Metabolic, mitochondrial, renal and hepatic safety of enfuvirtide and raltegravir antiretroviral administration: Randomized crossover clinical trial in healthy volunteers.

CONTEXT: Classical antiretroviral agents may acutely impact on metabolic, mitochondrial, renal and hepatic function in HIV-infected and uninfected persons. Fusion and integrase inhibitors are supposed to be safer, but have been scarcely investigated. To avoid any interference with HIV or other antiretrovirals, we assessed markers of these toxicities in healthy adult volunteers treated with Enfuvirtide (T20) or Raltegravir (RAL). METHODS: Twenty-six healthy participants were randomized to T20/90mg vs. placebo (n = 12) or RAL/400mg vs. placebo (n = 14) every 12h in two 7-day periods separated by a 4-week washout period. Major end-points were changes in lipid profile (total cholesterol, high-density-lipoprotein (HDL)-cholesterol, low-density-lipoprotein (LDL)-cholesterol, triglycerides), insulin resistance (glucose) and mitochondrial toxicity (mitochondrial DNA content-mtDNA-in peripheral blood mononuclear cells). Renal and hepatic toxicity (creatinine, alanine transaminase (AST), alanine aminotransferase (ALT), bilirubin and total plasma proteins) and overall safety were also analysed. Effect of period, treatment, and basal measures were evaluated for each end-point. RESULTS: Neither T20-administration nor RAL-administration yielded to any statistic significant change in the markers of metabolic, mitochondrial, renal or hepatic toxicity assessed. No symptoms indicative of drug toxicity were neither found in any subject. CONCLUSIONS: In absence of HIV infection, or concomitant treatment, short-term exposure to T20 or RAL in healthy adult volunteers did not lead to any indicative changes in toxicity markers thus presuming the safe profile of both drugs.

¿Es tiempo de plantear ensayos clínicos de bajo nivel de intervención sin el consentimiento informado de los participantes? / Is it time to discuss on low-intervention clinical trials without participants' informed consent?

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Memory Retrieval Re-Activates Erk1/2 Signaling in the Same Set of CA1 Neurons Recruited During Conditioning.

The hippocampus enables a range of behaviors through its intrinsic circuits and concerted actions with other brain regions. One such important function is the retrieval of episodic memories. How hippocampal cells support retrieval of contextual fear memory remains largely unclear. Here we monitored phospho-activation of extracellular-regulated kinase (Erk1/2) across neuronal populations of the hippocampus to find that CA1 pyramidal neurons, but not cells in CA3 or dentate gyrus, specifically respond to retrieval of an aversive context. In contrast, retrieval of a neutral context that fails to elicit a threat response did not activate Erk1/2. Moreover, retrieval preferentially re-activated Erk1/2 in the same set of CA1 neurons previously activated during conditioning in a context-specific manner. By confining drug inhibition within dorsal CA1, we established the crucial role for Erk1/2 activity in retrieval of long-term memory, as well as in amygdala activation associated with fear expression. These data provide functional evidence that Erk1/2 signaling in CA1 encodes a specific neural representation of contextual memory with emotional value.

Who is willing to participate in low-risk pragmatic clinical trials without consent?

PURPOSE: General notification offers a possible alternative to written informed consent for pragmatic randomized controlled trials (pRCTs). It involves patients being informed through brochures, posters, and letters that research is being conducted simultaneously to providing clinical care and that patients will be enrolled in pRCTs without study-specific consent. A previous survey found that a substantial minority of respondents endorsed general notification. We aimed to know who is willing to enroll in this type of trials using general notification rather than written consent. METHODS: The previous study was a cross-sectional, probability-based survey, with a 2 × 2 factorial design. Two scenarios were assessed: two low-risk pRCTs in hypertension, one comparing two drugs with similar benefit/risk ratio and the other taking the same drug in the morning or at night. Each scenario had two routes: written consent vs verbal consent and written consent vs general notification. In this study, we were interested in the latter route in both scenarios. Respondents' preferences were measured based on their recommendation to the research ethics committee and the respondent's personal preference. We aimed to investigate the characteristics of those supporting general notification in either outcome or the variables explaining consistency and inconsistency between their personal preference and their recommendation. Based on the results of the original survey, we aimed to have at least 200 inconsistent respondents; to this end, the sample size was increased accordingly in a second wave of the survey. RESULTS: One thousand six hundre and ten respondents were included; 1003 from the original survey and 607 new ones belonging to the second wave. Thirty-nine percent of respondents chose general notification as personal preference and/or recommendation. Respondents with lower education levels were more prone to accept general notification than those holding a university degree [OR (95% CI)], primary school [2.959 (2.069-4.232)], secondary school [2.899 (2.09-4.021)], or high school [1.620 (1.184-2.217)]. Also unemployed [1.372 (1.064-1.770)] and retired [1.445 (1.049-1.990)], but not students, showed preference for general notification in comparison with those employed. Individuals more than 24 years old and having received high school or university (or postgraduate) education were statistically significantly more consistent in their decisions. CONCLUSIONS: Thirty-nine percent of respondents is open to not to be asked for their informed consent in low-risk pRCTs; of these, those being less educated and not having current job or being retired are significantly more open to general notification. The use of this alternative method to written consent for simultaneous conduct of pRCTs and care should be considered and educational programs settled up to, in the case of public acceptance, ensure its ethical appropriateness.

Patients' beliefs regarding informed consent for low-risk pragmatic trials.

BACKGROUND: The requirement to obtain written informed consent may undermine the potential of pragmatic randomized clinical trials (pRCTs) to improve evidence-based care. This requirement could compromise trials statistical power or even force it to close them down prematurely. However, recent data from the U.S. and Spain suggest that a majority of the public endorses written consent for low-risk pRCTs. The present manuscript assesses whether this view is shared by patients. METHODS: This was a cross-sectional, probability-based survey, with a 2 × 2 factorial design, assessing support for written informed consent versus verbal consent or general notification for two low-risk pRCTs in hypertension, one comparing 2 drugs with similar risk/benefit profiles and the other comparing the same drug being taken in the morning or at night. This web-based survey was conducted in May 2016. Two-thousand and eight adults who were representative of the Spanish population participated in the survey (response rate: 61%). Of these 2008 respondents, 338 indicated that they had been diagnosed with hypertension and were being treated with prescription medicines for this condition at the time of responding to the survey. The primary outcome measures were respondents' personal preference and recommendation to a research ethics committee regarding the use of written informed consent versus verbal consent or general notification. RESULTS: Overall, 74% of the 338 patient respondents endorsed written consent. In both scenarios, general notification received significantly more support (30.6%-44.7%) than verbal consent (13.3%-17.6%). 43% of respondents preferred and/or recommended general notification rather than written consent. CONCLUSIONS: As in the survey of the general public, more patients endorsed written consent than the alternative option. However, two factors suggest that a different approach to written consent should be investigated for low-risk pRCTs: a) a substantial minority of respondents supported general notification, b) data from the US have shown that most patients who prefer written consent are willing to forego it if obtaining written consent makes the trial too difficult to be conducted; and c) 2016 CIOMS guidelines endorse waivers of consent when the trial fulfills specific conditions. Surveys in other EU countries are needed to assess what patients believe towards pRCTs. If similar results to that reported in this study are found, it is foreseeable that with educational efforts, general notification could be an acceptable and widespread approach to the conduct of low-risk pRCTs.

Public preferences on written informed consent for low-risk pragmatic clinical trials in Spain.

AIMS: Pragmatic randomized clinical trials (pRCTs) collect data that have the potential to improve medical care significantly. However, these trials may be undermined by the requirement to obtain written informed consent, which can decrease accrual and increase selection bias. Recent data suggest that the majority of the US public endorses written consent for low-risk pRCTs. The present study was designed to assess whether this view is specific to the US. METHODS: The study took the form of a cross-sectional, probability-based survey, with a 2 × 2 factorial design, assessing support for written informed consent vs. verbal consent or general notification for two low-risk pRCTs in hypertension, one comparing two drugs with similar risk/benefit profiles and the other comparing the same drug being taken in the morning or at night. The primary outcome measures were respondents' personal preference and hypothetical recommendation to a research ethics committee regarding the use of written informed consent vs. the alternatives. RESULTS: A total of 2008 adults sampled from a probability-based online panel responded to the web-based survey conducted in May 2016 (response rate: 61%). Overall, 77% of respondents endorsed written consent. In both scenarios, the alternative of general notification received significantly more support (28.7-37.1%) than the alternative of verbal consent (12.7-14.0%) (P = 0.001). Forty per cent of respondents preferred and/or recommended general notification rather than written consent. CONCLUSIONS: The results suggested that, rather than attempting to waive written consent, current pRCTs should focus on developing ways to implement written consent that provide sufficient information without undermining recruitment or increasing selection bias. The finding that around 40% of respondents endorsed general notification over written consent raises the possibility that, with educational efforts, the majority of Spaniards might accept general notification for low-risk pRCTs.

Ethical challenges in preclinical Alzheimer's disease observational studies and trials: Results of the Barcelona summit.

Alzheimer's disease (AD) is among the most significant health care burdens. Disappointing results from clinical trials in late-stage AD persons combined with hopeful results from trials in persons with early-stage suggest that research in the preclinical stage of AD is necessary to define an optimal therapeutic success window. We review the justification for conducting trials in the preclinical stage and highlight novel ethical challenges that arise and are related to determining appropriate risk-benefit ratios and disclosing individuals' biomarker status. We propose that to conduct clinical trials with these participants, we need to improve public understanding of AD using unified vocabulary, resolve the acceptable risk-benefit ratio in asymptomatic participants, and disclose or not biomarker status with attention to study type (observational studies vs clinical trials). Overcoming these challenges will justify clinical trials in preclinical AD at the societal level and aid to the development of societal and legal support for trial participants.

Dosing of rivaroxaban by indication: getting the right dose for the patient.

INTRODUCTION: Vitamin K antagonists were the only oral anticoagulants available for several decades, but they require frequent coagulation monitoring and dose adjustment. The direct oral anticoagulants rivaroxaban , dabigatran, apixaban, and, most recently, edoxaban have been approved for the management of specific thromboembolic indications. AREAS COVERED: This review will provide a brief overview of the cell-based coagulation model, the main determinants of arterial and venous thrombosis, and the pharmacological rationale and clinical evidence for the different dosing regimens of rivaroxaban. Published articles indexed on PubMed and Medline covering arterial and venous thrombi pathophysiology, pharmacokinetics, and pharmacodynamics of rivaroxaban, and Phase II and Phase III clinical studies with rivaroxaban as well as real-world evidence were analyzed. EXPERT OPINION: Education on pharmacokinetic/pharmacodynamic characteristics, as well as how to manage adverse events, is needed to increase physician knowledge and confidence in using direct oral anticoagulants, as specifically discussed for rivaroxaban in this article. The continued uptake of direct oral anticoagulants in clinical practice depends on understanding of the clinical evidence and reassurance provided by emerging real-world data.

Coagulation Factor Concentrates Fail to Restore Alterations in Fibrin Formation Caused by Rivaroxaban or Dabigatran in Studies With Flowing Blood From Treated Healthy Volunteers.

We evaluated the hemostatic alterations in blood from healthy individuals treated for 5 days with direct oral anticoagulants (DOACs) rivaroxaban (20 mg/d) or dabigatran (150 mg/12 h) in a single-blind clinical trial with crossover assignment (NCT01478282). We assessed the potential of prothrombin complex concentrates, activated prothrombin complex concentrates, or recombinant activated factor VII, when added ex vivo, to reverse the alterations caused by these DOACs. Blood was drawn at maximum plasma concentration after the last dose of each DOAC, and modifications in coagulation biomarkers were evaluated using a series of tests performed under steady conditions including routine coagulation, thrombin generation, and thromboelastometry assays. Additional studies in standardized flow devices were applied to evaluate alterations on platelet deposition and fibrin formation on damaged vascular surfaces exposed to flowing blood. Both DOACs caused important modifications of all coagulation biomarkers and significantly reduced fibrin formation in flow studies. Alterations in biomarkers observed in steady laboratory tests were normalized and occasionally overcompensated by procoagulant strategies. In contrast, reductions in fibrin formation observed in studies with flowing blood were improved, although never completely restored to baseline levels. Effects of dabigatran in flow studies appeared more resistant to reversal strategies than those of rivaroxaban. Inconsistencies between results of coagulation studies in steady or flowing assays not only raise concerns about the adequacy of the earlier tests to predict the restoration of the coagulopathy induced by DOACs but also suggest limitations of nonspecific procoagulant strategies to control severe coagulopathy in patients inadvertently overexposed these agents.

Reversal of rivaroxaban-induced alterations on hemostasis by different coagulation factor concentrates ­ in vitro studies with steady and circulating human blood.

BACKGROUND: Despite the good safety of rivaroxaban, there is limited information on strategies for urgent reversal of its antihemostatic effects. METHODS AND RESULTS: Alterations of hemostasis induced by rivaroxaban (230 ng/ml) were assessed by using several tests applied to steady and circulating human blood. Effects on thrombin generation (TG) and thromboelastometry (TEM) parameters were measured. Modifications in platelet adhesive, aggregating and procoagulant activities were evaluated in studies with circulating blood. The potential reversal of prothrombin complex concentrates (PCCs; 50 IU/kg), activated PCCs (aPCCs; 75 IU/kg), or recombinant factor VIIa (rFVIIa; 270 µg/kg) was evaluated. Impairment of TG parameters induced by rivaroxaban were corrected by the different concentrates (aPCC≥PCC>rFVIIa). Prolonged clotting times and reduced clot firmness caused by rivaroxaban on TEM tests were improved by different concentrates (rFVIIa≥aPCC>PCC). Rivaroxaban significantly reduced platelets and fibrin interactions with damaged vascular surfaces in perfusion studies. While alterations of platelet interactions were favourably counteracted by rFVIIa or aPCCs, reductions in fibrin formation were only partially restored by the different factor concentrates (rFVIIa>aPCC≥PCC). CONCLUSIONS: Rivaroxaban-induced alterations on coagulation parameters measured through assays performed under static conditions were easily reversed by the different concentrates. Studies under flow conditions revealed that these concentrates normalized the action of rivaroxaban on platelets, and significantly improved fibrin formation; although in the later case, levels were not restored to the pre-treatment value.

Safety and efficacy of uric acid in patients with acute stroke (URICO-ICTUS): a randomised, double-blind phase 2b/3 trial.

INTRODUCTION: Uric acid is an antioxidant with neuroprotective effects in experimental models of stroke. We assessed whether uric acid therapy would improve functional outcomes at 90 days in patients with acute ischaemic stroke. METHODS: URICO-ICTUS was a randomised, double-blind, placebo-controlled, phase 2b/3 trial that recruited patients with acute ischaemic stroke admitted to ten Spanish stroke centres. Patients were included if they were aged 18 years or older, had received alteplase within 4·5 h of symptom onset, and had an eligible National Institutes of Health Stroke Scale (NIHSS) score (>6 and ≤25) and premorbid (assessed by anamnesis) modified Rankin Scale (mRS) score (≤2). Patients were randomly allocated (1:1) to receive uric acid 1000 mg or placebo (both infused intravenously in 90 min during the infusion of alteplase), stratified by centre and baseline stroke severity. The primary outcome was the proportion of patients with excellent outcome (ie, an mRS score of 0-1, or 2 if premorbid score was 2) at 90 days, analysed in the target population (all randomly assigned patients who had been correctly diagnosed with ischaemic stroke and had begun study medication). The study is registered with ClinicalTrials.gov, number NCT00860366. FINDINGS: Between July 1, 2011, and April 30, 2013, we randomly assigned 421 patients, of whom 411 (98%) were included in the target population (211 received uric acid and 200 received placebo). 83 (39%) patients who received uric acid and 66 (33%) patients who received placebo had an excellent outcome (adjusted risk ratio 1·23 [95% CI 0·96-1·56]; p=0·099). No clinically relevant or statistically significant differences were reported between groups with respect to death (28 [13%] patients who received uric acid vs 31 [16%] who received placebo), symptomatic intracerebral haemorrhage (nine [4%] vs six [3%]), and gouty arthritis (one [<1%] vs four [2%]). 516 adverse events occurred in the uric acid group and 532 in the placebo group, of which 61 (12%) and 67 (13%), respectively, were serious adverse events (p=0·703). INTERPRETATION: The addition of uric acid to thrombolytic therapy did not increase the proportion of patients who achieved excellent outcome after stroke compared with placebo, but it did not lead to any safety concerns. FUNDING: Institute of Health Carlos III of the Spanish Ministry of Health and Fundación Doctor Melchor Colet.