Heterogeneity of treatment response to beta-blockers in the treatment of portal hypertension: A systematic review.

BACKGROUND: It has been suggested that a relevant proportion of patients do not respond to nonselective beta-blockers (NSBB)s, which raises questions regarding the need for individualized therapy. The existence of potential heterogeneity in the treatment response can be assessed using the variability ratio (VR) of the outcome measurement (in this case, HVPG) between the treated and placebo groups. We conducted a systematic review and meta-analysis of randomized controlled trials to assess the potential heterogeneity in the portal pressure response to NSBBs. METHODS: After a systematic search, we quantified the heterogeneity of treatment response with the VR between the treatment and control groups, with VR > 1 indicating potential heterogeneity. We used a similar approach to compare carvedilol with propranolol and statins with placebo. RESULTS: We identified 18 studies that included 965 patients. A comparison between beta-blockers and placebo showed a pooled VR of 0.99 (95% CI:0.87-1.14), which suggests a homogeneous HVPG response to NSBB at the individual patient level (ie, no evidence to support that some patients responded to beta-blockers and others did not). For the comparison between carvedilol and propranolol, pooled VR was 0.97 (95% CI 0.82-1.14), suggesting that carvedilol achieves a greater average response (rather than an increase in the proportion of responders). There was no evidence of a heterogeneous response to statins. CONCLUSION: Our analysis did not support the existence of a heterogeneous patient-by-patient response to NSBBs in cirrhosis. These findings challenge the concept of personalized therapy based on portal pressure response and indicate that routine portal pressure measurement may not be necessary to guide NSBB therapy.

Study protocol for a randomized controlled trial of Proportional Assist Ventilation for Minimizing the Duration of Mechanical Ventilation: the PROMIZING study.

BACKGROUND: Proportional assist ventilation with load-adjustable gain factors (PAV+) is a mechanical ventilation mode that delivers assistance to breathe in proportion to the patient's effort. The proportional assistance, called the gain, can be adjusted by the clinician to maintain the patient's respiratory effort or workload within a normal range. Short-term and physiological benefits of this mode compared to pressure support ventilation (PSV) include better patient-ventilator synchrony and a more physiological response to changes in ventilatory demand. METHODS: The objective of this multi-centre randomized controlled trial (RCT) is to determine if, for patients with acute respiratory failure, ventilation with PAV+ will result in a shorter time to successful extubation than with PSV. This multi-centre open-label clinical trial plans to involve approximately 20 sites in several continents. Once eligibility is determined, patients must tolerate a short-term PSV trial and either (1) not meet general weaning criteria or (2) fail a 2-min Zero Continuous Positive Airway Pressure (CPAP) Trial using the rapid shallow breathing index, or (3) fail a spontaneous breathing trial (SBT), in this sequence. Then, participants in this study will be randomized to either PSV or PAV+ in a 1:1 ratio. PAV+ will be set according to a target of muscular pressure. The weaning process will be identical in the two arms. Time to liberation will be the primary outcome; ventilator-free days and other outcomes will be measured. DISCUSSION: Meta-analyses comparing PAV+ to PSV suggest PAV+ may benefit patients and decrease healthcare costs but no powered study to date has targeted the difficult to wean patient population most likely to benefit from the intervention, or used consistent timing for the implementation of PAV+. Our enrolment strategy, primary outcome measure, and liberation approaches may be useful for studying mechanical ventilation and weaning and can offer important results for patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT02447692 . Prospectively registered on May 19, 2015.

Early and Delayed Infarct Growth in Patients Undergoing Mechanical Thrombectomy: A Prospective, Serial MRI Study.

BACKGROUND: We studied the evolution over time of diffusion weighted imaging (DWI) lesion volume and the factors involved on early and late infarct growth (EIG and LIG) in stroke patients undergoing endovascular treatment (EVT) according to the final revascularization grade. METHODS: This is a prospective cohort of patients with anterior large artery occlusion undergoing EVT arriving at 1 comprehensive stroke center. Magnetic resonance imaging was performed on arrival (pre-EVT), <2 hours after EVT (post-EVT), and on day 5. DWI lesions and perfusion maps were evaluated. Arterial revascularization was assessed according to the modified Thrombolysis in Cerebral Infarction (mTICI) grades. We recorded National Institutes of Health Stroke Scale at arrival and at day 7. EIG was defined as (DWI volume post-EVT-DWI volume pre-EVT), and LIG was defined as (DWI volume at 5d-DWI volume post-EVT). Factors involved in EIG and LIG were tested via multivariable lineal models. RESULTS: We included 98 patients (mean age 70, median National Institutes of Health Stroke Scale score 17, final mTICI≥2b 86%). Median EIG and LIG were 48 and 63.3 mL in patients with final mTICI<2b, and 3.6 and 3.9 cc in patients with final mTICI≥2b. Both EIG and LIG were associated with higher National Institutes of Health Stroke Scale at day 7 (ρ=0.667; P<0.01 and ρ=0.614; P<0.01, respectively). In patients with final mTICI≥2b, each 10% increase in the volume of DWI pre-EVT and each extra pass leaded to growths of 9% (95% CI, 7%-10%) and 14% (95% CI, 2%-28%) in the DWI volume post-EVT, respectively. Furthermore, each 10% increase in the volume of DWI post-EVT, each extra pass, and each 10 mL increase in TMax6s post-EVT were associated with growths of 8% (95% CI, 6%-9%), 9% (95% CI, 0%-19%), and 12% (95% CI, 5%-20%) in the volume of DWI post-EVT, respectively. CONCLUSIONS: Infarct grows during and after EVT, especially in nonrecanalizers but also to a lesser extent in recanalizers. In recanalizers, number of passes and DWI volume influence EIG, while number of passes, DWI, and hypoperfused volume after the procedure determine LIG.

Use of GPS to measure external load and estimate the incidence of muscle injuries in men's football: A novel descriptive study.

Measurement of external load in players provides objective information to optimise the weekly balance between training and recovery to improve performance and prevent injuries. Our aim was to evaluate the incidence of sports-related muscle injuries of the lower limb in relation to external load, measured by global positioning system (GPS), in football players. A descriptive study was carried out. Data were collected from 71 professional male football players (30 professionals and 41 youth players) from an elite football club competing in the Spanish and European League in the 2017-2018 season. As external load variables, we measured High Metabolic Load Distance (HMLD), High Speed Running (HSR), Player Load (PL), and Total Distance (TD) through GPS. Injury rate (IR) was calculated both in relation to such GPS load metrics and to load exposure time. We considered categories (youth and professional), playing positions (centre back, full back, midfielder, and forward), and training day with respect to match-day (-4MD, -3MD, -2MD, -1MD, MD, +1MD, +2MD). The GPS load metrics HMLD, HSR, PL, and TD showed very similar patterns across categories and positions, but varied according to training session or MD. The highest loads were observed on MD and three days prior to the match (-3MD). Similarly, the overall IR, both calculated per load exposure time and per GPS load metrics, was highest on MD and -3MD. Again, no differences were observed between youth and professional players. Midfielders demonstrated the highest IR in all metrics, followed by the forwards. In conclusion, this study suggests that external load and incidence of muscle injuries are directly proportional. Therefore, the measurement of more external load variables other than load exposure time, such as the GPS metrics HMLD, HSR, PL, and TD may help to describe the pattern and magnitude of injuries. Future studies based on ours may help to further improve the understanding of the incidence of muscle injuries on the basis of external loads measurements in different football teams.

Effect of Rashba and Dresselhaus spin-orbit coupling on supercurrent rectification and magnetochiral anisotropy of ballistic Josephson junctions.

Simultaneous breaking of inversion- and time-reversal symmetry in Josephson junction (JJ) leads to a possible violation of theI(φ) = -I(-φ) equality for the current-phase relation. This is known as anomalous Josephson effect and it produces a phase shiftφ0in sinusoidal current-phase relations. In ballistic JJs with non-sinusoidal current phase relation the observed phenomenology is much richer, including the supercurrent diode effect and the magnetochiral anisotropy (MCA) of Josephson inductance. In this work, we present measurements of both effects on arrays of JJs defined on epitaxial Al/InAs heterostructures. We show that the orientation of the current with respect to the lattice affects the MCA, possibly as the result of a finite Dresselhaus component. In addition, we show that the two-fold symmetry of the Josephson inductance reflects in the activation energy for phase slips.

Targeting Pro-Oxidant Iron with Deferoxamine as a Treatment for Ischemic Stroke: Safety and Optimal Dose Selection in a Randomized Clinical Trial.

A role of iron as a target to prevent stroke-induced neurodegeneration has been recently revisited due to new evidence showing that ferroptosis inhibitors are protective in experimental ischemic stroke and might be therapeutic in other neurodegenerative brain pathologies. Ferroptosis is a new form of programmed cell death attributed to an overwhelming lipidic peroxidation due to excessive free iron and reactive oxygen species (ROS). This study aims to evaluate the safety and tolerability and to explore the therapeutic efficacy of the iron chelator and antioxidant deferoxamine mesylate (DFO) in ischemic stroke patients. Administration of placebo or a single DFO bolus followed by a 72 h continuous infusion of three escalating doses was initiated during the tPA infusion, and the impact on blood transferrin iron was determined. Primary endpoint was safety and tolerability, and secondary endpoint was good clinical outcome (clinicalTrials.gov NCT00777140). DFO was found safe as adverse effects were not different between placebo and DFO arms. DFO (40-60 mg/Kg/day) reduced the iron saturation of blood transferrin. A trend to efficacy was observed in patients with moderate-severe ischemic stroke (NIHSS > 7) treated with DFO 40-60 mg/Kg/day. A good outcome was observed at day 90 in 31% of placebo vs. 50-58% of the 40-60 mg/Kg/day DFO-treated patients.

The use and adherence of oral anticoagulants in Primary Health Care in Catalunya, Spain: A real-world data cohort study / Uso y adherencia a los anticoagulantes orales en Atención Primaria en Cataluña, España: estudio de cohortes con datos procedentes de registros electrónicos de salud

OBJECTIVE: We aimed to describe sociodemographic, comorbidities, co-medication and risk of thromboembolic events and bleeding in patients with NVAF initiating oral anticoagulants (OAC) for stroke prevention, and to estimate adherence and persistence to OAC. SETTING: Primary Health Care (PHC) in the Catalan Health Institute (ICS), Catalunya, Spain. PARTICIPANTS: All NVAF adult patients initiating OAC for stroke prevention in August 2013-December 2015. METHODS: Population-based cohort study. Persistence was measured in patients initiating OAC in August 2013-December 2014. Data source: SIDIAP, which captures electronic health records from PHC in the (ICS), covering approximately 5.8 million people. RESULTS: 51,690 NVAF patients initiated OAC; 47,197 (91.3%) were naive to OAC and 32,404 (62.7%) initiated acenocoumarol. Mean age was 72.8 years (SD 12.3) and 49.4% were women. Platelet-aggregation inhibitors were taken by 9105 (17.6%) of the patients. Persistence and adherence were estimated up to the end of follow-up. For 22,075 patients, persistence was higher among the non-naive patients [n = 258 (61.7%)] than among the naive [n = 11,502 (53.1%)]. Adherence was estimated for patients initiating DOAC and it was similar in naive and non-naive patients. Among the naive to DOAC treatment, those starting rivaroxaban showed a highest proportion [(n = 360 (80.1%)] of good adherence at implementation (MPR>80%) while patients starting dabigatran were less adherent [n = 203 (47.8%)]. CONCLUSIONS: Acenocoumarol was the most frequently prescribed OAC as first therapy in NVAF patients. Non-naive to DOAC showed better persistence than naive. Rivaroxaban showed higher proportion of adherent patients during the implementation phase than apixaban and dabigatran the lowest

OBJETIVO: Describir datos sociodemográficos, comorbilidades, comedicaciones y riesgo de eventos tromboembólicos y hemorrágicos de los pacientes con fibrilación auricular no valvular (FANV) que inician tratamiento anticoagulante por vía oral (TAO) para prevención del ictus. Estimar adherencia y persistencia al TAO. EMPLAZAMIENTO: Atención primaria (AP) del Instituto Catalán de Salud (ICS), Cataluña, España. PARTICIPANTES: Adultos con FANV que inician TAO para prevención de ictus entre agosto del 2013 y diciembre del 2015. MÉTODOS: Estudio de cohortes de base poblacional. Adherencia y persistencia se midieron en pacientes que iniciaban TAO entre agosto del 2013 y diciembre del 2014. Fuente de datos: SIDIAP, base de datos procedentes de registros electrónicos de AP del ICS, que cubre aproximadamente una población de 5,8 millones de personas. RESULTADOS: Cincuenta y un mil seiscientos noventa pacientes con FANV iniciaron TAO, 47.197 (91,3%) eran naïve al TAO y 32.404 (62,7%) iniciaron acenocumarol. Su edad media era 72,8 años (DE 12,3) y el 49,4% eran mujeres; 90105 (17,6%) recibían tratamiento antiagregante plaquetario. Persistencia y adherencia se estimaron hasta el final del seguimiento. La persistencia a anticoagulantes orales directos (ACOD) fue mayor en no naïve que en naïve (61,7% vs. 53,1%). La adherencia a ACOD fue similar en los 2 grupos. Entre los naïve, los pacientes que iniciaban rivaroxabán (80,1%) mostraron mayor adherencia en la implementación (MPR > 80%), mientras que los que iniciaban dabigatrán fueron menos adherentes (47,8%). CONCLUSIONES: Acenocumarol fue el anticoagulante más prescrito. Los pacientes no naïve mostraron mejor persistencia al tratamiento que los naïve. Rivaroxabán mostró mayores tasas de adherencia que apixabán y dabigatrán, las menores

The use and adherence of oral anticoagulants in Primary Health Care in Catalunya, Spain: A real-world data cohort study.

OBJECTIVE: We aimed to describe sociodemographic, comorbidities, co-medication and risk of thromboembolic events and bleeding in patients with NVAF initiating oral anticoagulants (OAC) for stroke prevention, and to estimate adherence and persistence to OAC. SETTING: Primary Health Care (PHC) in the Catalan Health Institute (ICS), Catalunya, Spain. PARTICIPANTS: All NVAF adult patients initiating OAC for stroke prevention in August 2013-December 2015. METHODS: Population-based cohort study. Persistence was measured in patients initiating OAC in August 2013-December 2014. DATA SOURCE: SIDIAP, which captures electronic health records from PHC in the (ICS), covering approximately 5.8 million people. RESULTS: 51,690 NVAF patients initiated OAC; 47,197 (91.3%) were naive to OAC and 32,404 (62.7%) initiated acenocoumarol. Mean age was 72.8 years (SD 12.3) and 49.4% were women. Platelet-aggregation inhibitors were taken by 9105 (17.6%) of the patients. Persistence and adherence were estimated up to the end of follow-up. For 22,075 patients, persistence was higher among the non-naive patients [n=258 (61.7%)] than among the naive [n=11,502 (53.1%)]. Adherence was estimated for patients initiating DOAC and it was similar in naive and non-naive patients. Among the naive to DOAC treatment, those starting rivaroxaban showed a highest proportion [(n=360 (80.1%)] of good adherence at implementation (MPR>80%) while patients starting dabigatran were less adherent [n=203 (47.8%)]. CONCLUSIONS: Acenocoumarol was the most frequently prescribed OAC as first therapy in NVAF patients. Non-naive to DOAC showed better persistence than naive. Rivaroxaban showed higher proportion of adherent patients during the implementation phase than apixaban and dabigatran the lowest.

Validity of ICD-9 and ICD-10 codes used to identify acute liver injury: A study in three European data sources.

PURPOSE: Validating cases of acute liver injury (ALI) in health care data sources is challenging. Previous validation studies reported low positive predictive values (PPVs). METHODS: Case validation was undertaken in a study conducted from 2009 to 2014 assessing the risk of ALI in antidepressants users in databases in Spain (EpiChron and SIDIAP) and the Danish National Health Registers. Three ALI definitions were evaluated: primary (specific hospital discharge codes), secondary (specific and nonspecific hospital discharge codes), and tertiary (specific and nonspecific hospital and outpatient codes). The validation included review of patient profiles (EpiChron and SIDIAP) and of clinical data from medical records (EpiChron and Denmark). ALI cases were confirmed when liver enzyme values met a definition by an international working group. RESULTS: Overall PPVs (95% CIs) for the study ALI definitions were, for the primary ALI definition, 84% (60%-97%) (EpiChron), 60% (26%-88%) (SIDIAP), and 74% (60%-85%) (Denmark); for the secondary ALI definition, 65% (45%-81%) (EpiChron), 40% (19%-64%) (SIDIAP), and 70% (64%-77%) (Denmark); and for the tertiary ALI definition, 25% (18%-34%) (EpiChron), 8% (7%-9%) (SIDIAP), and 47% (42%-52%) (Denmark). The overall PPVs were higher for specific than for nonspecific codes and for hospital discharge than for outpatient codes. The nonspecific code "unspecified jaundice" had high PPVs in Denmark. CONCLUSIONS: PPVs obtained apply to patients using antidepressants without preexisting liver disease or ALI risk factors. To maximize validity, studies on ALI should prioritize hospital specific discharge codes and should include hospital codes for unspecified jaundice. Case validation is required when ALI outpatient cases are considered.

Adherence to reporting guidelines increases the number of citations: the argument for including a methodologist in the editorial process and peer-review.

BACKGROUND: From 2005 to 2010, we conducted 2 randomized studies on a journal (Medicina Clínica), where we took manuscripts received for publication and randomly assigned them to either the standard editorial process or to additional processes. Both studies were based on the use of methodological reviewers and reporting guidelines (RG). Those interventions slightly improved the items reported on the Manuscript Quality Assessment Instrument (MQAI), which assesses the quality of the research report. However, masked evaluators were able to guess the allocated group in 62% (56/90) of the papers, thus presenting a risk of detection bias. In this post-hoc study, we analyse whether those interventions that were originally designed for improving the completeness of manuscript reporting may have had an effect on the number of citations, which is the measured outcome that we used. METHODS: Masked to the intervention group, one of us used the Web of Science (WoS) to quantify the number of citations that the participating manuscripts received up December 2016. We calculated the mean citation ratio between intervention arms and then quantified the uncertainty of it by means of the Jackknife method, which avoids assumptions about the distribution shape. RESULTS: Our study included 191 articles (99 and 92, respectively) from the two previous studies, which all together received 1336 citations. In both studies, the groups subjected to additional processes showed higher averages, standard deviations and annual rates. The intervention effect was similar in both studies, with a combined estimate of a 43% (95% CI: 3 to 98%) increase in the number of citations. CONCLUSIONS: We interpret that those effects are driven mainly by introducing into the editorial process a senior methodologist to find missing RG items. Those results are promising, but not definitive due to the exploratory nature of the study and some important caveats such as: the limitations of using the number of citations as a measure of scientific impact; and the fact that our study is based on a single journal. We invite journals to perform their own studies to ascertain whether or not scientific repercussion is increased by adhering to reporting guidelines and further involving statisticians in the editorial process.

Transfer to the Local Stroke Center versus Direct Transfer to Endovascular Center of Acute Stroke Patients with Suspected Large Vessel Occlusion in the Catalan Territory (RACECAT): Study protocol of a cluster randomized within a cohort trial.

RATIONALE: Optimal pre-hospital delivery pathways for acute stroke patients suspected to harbor a large vessel occlusion have not been assessed in randomized trials. AIM: To establish whether stroke subjects with rapid arterial occlusion evaluation scale based suspicion of large vessel occlusion evaluated by emergency medical services in the field have higher rates of favorable outcome when transferred directly to an endovascular center (endovascular treatment stroke center), as compared to the standard transfer to the closest local stroke center (local-SC). DESIGN: Multicenter, superiority, cluster randomized within a cohort trial with blinded endpoint assessment. PROCEDURE: Eligible patients must be 18 or older, have acute stroke symptoms and not have an immediate life threatening condition requiring emergent medical intervention. They must be suspected to have intracranial large vessel occlusion based on a pre-hospital rapid arterial occlusion evaluation scale of ≥5, be located in geographical areas where the default health authority assigned referral stroke center is a non-thrombectomy capable hospital, and estimated arrival at a thrombectomy capable stroke hospital in less than 7 h from time last seen well. Cluster randomization is performed according to a pre-established temporal sequence (temporal cluster design) with three strata: day/night, distance to the endovascular treatment stroke center, and week/week-end day. STUDY OUTCOME: The primary endpoint is the modified Rankin Scale score at 90 days. The primary safety outcome is mortality at 90 days. ANALYSIS: The primary endpoint based on the modified intention-to-treat population is the distribution of modified Rankin Scale scores at 90 days analyzed under a sequential triangular design. The maximum sample size is 1754 patients, with two planned interim analyses when 701 (40%) and 1227 patients have completed follow-up. Hypothesized common odds ratio is 1.35.

Risk of Acute Liver Injury in Agomelatine and Other Antidepressant Users in Four European Countries: A Cohort and Nested Case-Control Study Using Automated Health Data Sources.

BACKGROUND: Agomelatine is a melatonin receptor agonist and serotonin 5-HT2C receptor antagonist indicated for depression in adults. Hepatotoxic reactions like acute liver injury (ALI) are an identified risk in the European risk management plan for agomelatine. Hepatotoxic reactions have been reported for other antidepressants, but population studies quantifying these risks are scarce. Antidepressants are widely prescribed, and users often have risk factors for ALI (e.g. metabolic syndrome). OBJECTIVE: The goal was to estimate the risk of ALI associated with agomelatine and other antidepressants (fluoxetine, paroxetine, sertraline, escitalopram, mirtazapine, venlafaxine, duloxetine, and amitriptyline) when compared with citalopram in routine clinical practice. METHOD: A nested case-control study was conducted using data sources in Denmark, Germany, Spain, and Sweden (study period 2009-2014). Three ALI endpoints were defined using International Classification of Diseases (ICD) codes: primary (specific codes) and secondary (all codes) endpoints used only hospital discharge codes; the tertiary endpoint included both inpatient and outpatient settings (all codes). Validation of endpoints was implemented. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for current use were estimated for each data source and combined. RESULTS: We evaluated 3,238,495 new antidepressant and 74,440 agomelatine users. For the primary endpoint, the OR for agomelatine versus citalopram was 0.48 (CI 0.13-1.71). Results were also < 1 when no exclusion criteria were applied (OR 0.37; CI 0.19-0.74), when all exclusion criteria except alcohol and drug abuse were applied (OR 0.47; CI 0.20-1.07), and for the secondary (OR 0.40; CI 0.05-3.11) and tertiary (OR 0.79; CI 0.50-1.25) endpoints. Regarding other antidepressants versus citalopram, most OR point estimates were also below one, although with varying widths of the 95% CIs. The result of the tertiary endpoint and the sensitivity analyses of the primary endpoint were the most precise. CONCLUSION: In this study, using citalopram as a comparator, agomelatine was not associated with an increased risk of ALI hospitalisation. The results for agomelatine should be interpreted in the context of the European risk minimisation measures in place. Those measures may have induced selective prescribing and could explain the lower risk of ALI for agomelatine when compared with citalopram. Most other antidepressants evaluated had ORs suggesting a lower risk than citalopram, but additional studies are required to confirm or refute these results.

Antidepressant use in Denmark, Germany, Spain, and Sweden between 2009 and 2014: Incidence and comorbidities of antidepressant initiators.

BACKGROUND: We aimed to describe patterns of use and characteristics of 10 commonly used antidepressants for the period 2009-2014 in Denmark, Germany, Spain, and Sweden. METHODS: Adult initiators from 2009 to 2014 of each study antidepressant were identified in four countries using five data sources: the Danish National registers, GePaRD (Germany), EpiChron (Aragon, Spain), SIDIAP (Catalonia, Spain), and the Swedish National Registers. The study included 10 study antidepressants: citalopram, escitalopram, fluoxetine, paroxetine, sertraline, duloxetine, venlafaxine, amitriptyline, mirtazapine, and agomelatine. RESULTS: Citalopram was the most prescribed study antidepressant, followed by mirtazapine. Paroxetine and agomelatine were the least prescribed antidepressants. Mirtazapine was widely used among older antidepressant initiators with higher percentages of comorbidities at baseline, and fluoxetine was used among young patients. Citalopram and amitriptyline had the lowest percentage of multiple antidepressant use in the 12 months prior to the current treatment episode, while agomelatine, duloxetine, and venlafaxine had the highest percentage of multiple antidepressant use in the year prior to the current treatment episode. LIMITATIONS: The most important limitations are exposure information based on filled prescriptions, focus on antidepressant initiators only, lack of information on the indication, and heterogeneity of the type of data across data sources. CONCLUSIONS: Results of this study including 4.8 million study antidepressant initiators of study antidepressants suggest that citalopram and mirtazapine are the most commonly prescribed antidepressants. Agomelatine and paroxetine were the least used antidepressants in the participating populations. Mirtazapine was the antidepressant most commonly prescribed among older antidepressant initiators with high percentage of comorbidities at baseline, whereas fluoxetine was commonly used among young patients.

Efficacy of high doses of penicillin versus amoxicillin in the treatment of uncomplicated community acquired pneumonia in adults. A non-inferiority controlled clinical trial / Eficacia de dosis altas de penicilina frente a amoxicilina en el tratamiento de la neumonía no complicada adquirida en la comunidad en adultos. Ensayo clínico controlado de no inferioridad

Introduction: Community-acquired pneumonia (CAP) is treated with penicillin in some northern European countries. Objectives: To evaluate whether high-dose penicillin V is as effective as high-dose amoxicillin for the treatment of non-severe CAP. Design: Multicentre, parallel, double-blind, controlled, randomized clinical trial. Setting: 31 primary care centers in Spain. Participants: Patients from 18 to 75 years of age with no significant associated comorbidity and with symptoms of lower respiratory tract infection and radiological confirmation of CAP were randomized to receive either penicillin V 1.6 million units, or amoxicillin 1000mg three times per day for 10 days. Main measurements: The main outcome was clinical cure at 14 days, and the primary hypothesis was that penicillin V would be non-inferior to amoxicillin with regard to this outcome, with a margin of 15% for the difference in proportions. EudraCT register 2012-003511-63. Results: A total of 43 subjects (amoxicillin: 28; penicillin: 15) were randomized. Clinical cure was observed in 10 (90.9%) patients assigned to penicillin and in 25 (100%) patients assigned to amoxicillin with a difference of -9.1% (95% CI, --41.3% to 6.4%; p = .951) for non-inferiority. In the intention-to-treat analysis, amoxicillin was found to be 28.6% superior to penicillin (95% CI, 7.3-58.1%; p = .009 for superiority). The number of adverse events was similar in both groups. Conclusions: There was a trend favoring high-dose amoxicillin versus high-dose penicillin in adults with uncomplicated CAP. The main limitation of this trial was the low statistical power due to the low number of patients included

Introducción: En algunos países la neumonía adquirida en la comunidad (NAC) se trata con penicilina. Objetivo: Evaluar si penicilina V a dosis altas es igual de efectiva que amoxicilina a dosis altas en la NAC no complicada. Diseño. Ensayo clínico paralelo, doble ciego, controlado y multicéntrico. Emplazamiento: Treinta y un centros de salud en España. Participantes: Se reclutaron pacientes de 18 a 75 años de edad sin comorbilidad asociada importante, con síntomas de infección respiratoria inferior y confirmación radiológica de neumonía, que fueron asignados aleatoriamente a 1,6M unidades de penicilina V o amoxicilina 1.000 mg, 3 veces al día, durante 10 días. Mediciones principales: La variable de resultado principal fue curación clínica a los 14 días y se planteó la hipótesis de que penicilina no era inferior a amoxicilina con un margen de 15% para la diferencia de proporciones. Registro EudraCT 2012-003511-63. Resultados: Se aleatorizaron 43 personas (amoxicilina: 28; penicilina: 15). Se observó curación clínica en 10 pacientes asignados a penicilina (90,9%) y en 25 asignados a amoxicilina (100%), observándose una diferencia de -9,1% (IC 95%: -41,3 a 6,4%; p = 0,951) para no inferioridad. En el análisis por intención de tratar amoxicilina fue 28,6% superior a penicilina V (IC 95%: 7,3% a 58,1%; p = 0,009 para superioridad). El número de eventos adversos fue similar en ambos grupos. Conclusiones: Se observó una tendencia de un mayor beneficio de amoxicilina frente a penicilina en adultos con NAC no complicada. La principal limitación fue la baja potencia estadística debido al bajo número de pacientes incluidos

Efficacy of high doses of penicillin versus amoxicillin in the treatment of uncomplicated community acquired pneumonia in adults. A non-inferiority controlled clinical trial.

INTRODUCTION: Community-acquired pneumonia (CAP) is treated with penicillin in some northern European countries. OBJECTIVES: To evaluate whether high-dose penicillin V is as effective as high-dose amoxicillin for the treatment of non-severe CAP. DESIGN: Multicentre, parallel, double-blind, controlled, randomized clinical trial. SETTING: 31 primary care centers in Spain. PARTICIPANTS: Patients from 18 to 75 years of age with no significant associated comorbidity and with symptoms of lower respiratory tract infection and radiological confirmation of CAP were randomized to receive either penicillin V 1.6 million units, or amoxicillin 1000mg three times per day for 10 days. MAIN MEASUREMENTS: The main outcome was clinical cure at 14 days, and the primary hypothesis was that penicillin V would be non-inferior to amoxicillin with regard to this outcome, with a margin of 15% for the difference in proportions. EudraCT register 2012-003511-63. RESULTS: A total of 43 subjects (amoxicillin: 28; penicillin: 15) were randomized. Clinical cure was observed in 10 (90.9%) patients assigned to penicillin and in 25 (100%) patients assigned to amoxicillin with a difference of -9.1% (95% CI, -41.3% to 6.4%; p=.951) for non-inferiority. In the intention-to-treat analysis, amoxicillin was found to be 28.6% superior to penicillin (95% CI, 7.3-58.1%; p=.009 for superiority). The number of adverse events was similar in both groups. CONCLUSIONS: There was a trend favoring high-dose amoxicillin versus high-dose penicillin in adults with uncomplicated CAP. The main limitation of this trial was the low statistical power due to the low number of patients included.

Characteristics of Apixaban-Treated Patients, Evaluation of the Dose Prescribed, and the Persistence of Treatment: A Cohort Study in Catalonia.

BACKGROUND: Apixaban is a direct oral anticoagulant, which inhibits factor Xa. It has demonstrated clinical efficacy in prevention of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation and a better safety profile compared to warfarin. OBJECTIVES: (1) To describe the characteristics of patients with nonvalvular atrial fibrillation beginning treatment with apixaban, (2) to analyze concomitant prescriptions of medications that could potentially interact with apixaban, (3) to evaluate the level of appropriate usage according to the recommended dosage, and (4) to estimate the level of apixaban persistence among naive and non-naive patients. METHODS: Cohort study using data from primary care (System for Research in Primary Care database, users of the Institut Català de la Salut; Catalonia, Spain) from August 2013 to December 2015. RESULTS: Mean age for apixaban-treated patients was 71.8 years (standard deviation = 11.1) and 55.6% were male. In all, 3.2% of patients receiving apixaban were taking drugs described as potentially related to either pharmacokinetic or pharmacodynamic interactions. According to the summary of product characteristics, 81.1% of patients with a recommended dose of 2.5 mg twice daily and 51.8% with a recommended dose of 5 mg twice daily actually took this dose. After 1 year of follow-up, 62.6% of the apixaban users showed good adherence. CONCLUSION: The prescribed dose of apixaban did not fully follow the recommended dose, particularly in patients who were treatment naive. Patients with a prior history of anticoagulant treatment were more likely to remain persistent to treatment with apixaban.

Impact of Medication Adherence on Mortality and Cardiovascular Morbidity: Protocol for a Population-Based Cohort Study.

BACKGROUND: Cardiovascular disease (CVD) is a group of disorders of the heart and blood vessels, such as coronary heart disease (CHD), cerebrovascular disease, and peripheral artery disease. CVD is the leading threat to global health, whether measured by mortality, morbidity, or economic cost. Long-term administration of aspirin, statins, beta-blockers, and angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers improves survival in patients with stablished coronary heart disease. Nevertheless, adherence to prescribed medication is poor for long-term drug treatment. OBJECTIVE: We aim to assess the relationship between adherences to the four pharmacological groups recommended for secondary prevention and the clinical outcomes of cardiovascular morbidity and mortality in patients with established CHD according to the level of adherence to these drugs in a population of incident cases of acute coronary syndrome (ACS). METHODS: Population-based cohort study of patients with a first episode of ACS during 2006-2015 in the Information System for Research in Primary Care (SIDIAP) database. We will estimate adherence to these drugs. The primary endpoint is a composite of all-cause mortality, ACS, and ischaemic stroke. Bivariate analyses will be performed estimating odds ratios for categorical variables and mean differences for continuous variables. Hazard ratios for adherences will be calculated for outcome events using Cox proportional hazard regression models, and proportionality of hazards assumption will be tested. RESULTS: We expect to estimate adherence to all four study treatments, the incidence of MACE, and to analyze if this incidence is associated with the level of drug adherence. CONCLUSIONS: We expect to find that adherent patients have a lower risk of the primary endpoints compared with nonadherent patients. TRIAL REGISTRATION: This study protocol was classified as EPA-OD by the AEMPS (IJG-EST-2017-01-2017-01, 07/04/2017) and registered in the EU PAS register (EUPAS19017, 09/05/2017).

Does evidence support the high expectations placed in precision medicine? A bibliographic review.

Background: Precision medicine is the Holy Grail of interventions that are tailored to a patient's individual characteristics. However, conventional clinical trials are designed to find differences in averages, and interpreting these differences depends on untestable assumptions. Although only an ideal, a constant effect of treatment would facilitate individual management. A direct consequence of a constant effect is that the variance of the outcome measure would be the same in the treated and control arms. We reviewed the literature to explore the similarity of these variances as a foundation for examining whether and how often precision medicine is definitively required. Methods: We reviewed parallel clinical trials with numerical primary endpoints published in 2004, 2007, 2010 and 2013. We collected the baseline and final standard deviations of the main outcome measure. We assessed homoscedasticity by comparing the variance of the primary endpoint between arms through the outcome variance ratio (treated to control group). Results: The review provided 208 articles with enough information to conduct the analysis. One out of five studies (n = 40, 19.2%) had statistically different variances between groups, implying a non-constant-effect. The adjusted point estimate of the mean outcome variance ratio (treated to control group) is 0.89 (95% CI 0.81 to 0.97). Conclusions: The mean variance ratio is significantly lower than 1 and the lower variance was found more often in the intervention group than in the control group, suggesting it is more usual for treated patients to be stable. This observed reduction in variance might also imply that there could be a subgroup of less ill patients who derive no benefit from treatment. This would require further study as to whether the treatment effect outweighs the side effects as well as the economic costs. We have shown that there are ways to analyze the apparently unobservable constant effect.

Predictive Value of Modifications of the Prehospital Rapid Arterial Occlusion Evaluation Scale for Large Vessel Occlusion in Patients with Acute Stroke.

BACKGROUND: Prehospital clinical scales to identify patients with acute stroke with a large vessel occlusion (LVO) and direct them to an endovascular-capable stroke center are needed. We evaluated whether simplification of the Rapid Arterial oCclusion Evaluation (RACE) scale, a 5-item scale previously validated in the field, could maintain its high performance to identify patients with LVO. METHODS: Using the original prospective validation cohort of the RACE scale, 7 simpler versions of the RACE scale were designed and retrospectively recalculated for each patient. National Institutes of Health Stroke Scale score and proximal LVO were evaluated in hospital. Receiver operating characteristic analysis was performed to test performance of the simplified versions to identify LVO. For each version, the threshold with sensitivity closest to the original scale (85%) was used, and the variation in specificity and correct classification were assessed. RESULTS: The study included 341 patients with suspected stroke; 20% had LVO. The 7 simpler versions of the RACE scale had slightly lower area under the curve for detecting LVO because of lower specificity at the chosen sensitivity level. Correct classification rate decreased 9% if facial palsy was simplified or if eye or gaze deviation was removed, and decreased 4.5% if the aphasia or agnosia cortical sign was removed. CONCLUSIONS: We recommend the original RACE scale for prehospital assessment of patients with suspected stroke for its ease of use and its high performance to predict the presence of a LVO. The use of simplified versions would reduce its predictive value.

Reported Prestroke Physical Activity Is Associated with Vascular Endothelial Growth Factor Expression and Good Outcomes after Stroke.

INTRODUCTION: Physical activity (PhA) prior to stroke has been associated with good outcomes after the ischemic insult, but there is scarce data on the involved molecular mechanisms. METHODS: We studied consecutive acute ischemic stroke patients admitted to a single tertiary stroke center. Prestroke PhA was evaluated with the International Physical Activity Questionnaire (metabolic equivalent of minutes/week). We studied several circulating angiogenic and neurogenic factors at different time points: vascular endothelial growth factor (VEGF), granulocyte colony-stimulating factor (G-CSF), and brain-derived neurotrophic factor (BDNF) at admission, day 7, and at 3 months. We considered good functional outcome at 3 months (modified Rankin scale ≤ 2) as primary end point, and final infarct volume as secondary outcome. RESULTS: We studied 83 patients with at least 2 time point serum determinations (mean age 69.6 years, median National Institutes of Health Stroke Scale 17 at admission). Patients more physically active before stroke had a significantly higher increment of serum VEGF on the seventh day when compared to less active patients. This increment was an independent predictor of good functional outcome at 3 months and was associated with smaller infarct volume in multivariate analyses adjusted for relevant covariates. We did not find independent associations of G-CSF or BDNF levels neither with level of prestroke PhA nor with stroke outcomes. CONCLUSIONS: Although there are probably more molecular mechanisms by which PhA exerts its beneficial effects in stroke outcomes, our observation regarding the potential role of VEGF is plausible and in line with previous experimental studies. Further research in this field is needed.