Direct oral anticoagulants for stroke prevention in patients with atrial fibrillation: meta-analysis by geographic region with a focus on European patients.

AIMS: To analyse clinical outcomes with direct oral anticoagulants in patients with atrial fibrillation according to geographic region. METHODS: We systematically searched MEDLINE, CENTRAL, websites of regulatory agencies, clinical trials registers and conference proceedings for randomized controlled trials of direct oral anticoagulants (DOAC: dabigatran, rivaroxaban, apixaban or edoxaban) against warfarin for prophylaxis of stroke and systemic embolic events (SEE) in patients with atrial fibrillation (AF). Two investigators independently extracted data. Relative risks of stroke and SEE as well as major bleeding depending on geographic region were estimated using a random effect meta-analysis. RESULTS: Five trials in 72 963 patients were analysed; 32 089 (44%) patients were recruited in Europe (Western Europe: 13 676; Eastern Europe: 18 413). We found significant subgroup differences for stroke/SEE depending on the geographic region (interaction P = 0.003; I(2) 88.5%), with a neutral effect of the DOAC vs. warfarin in Europe [relative risk (RR) 0.97, 95% confidence interval (CI) 0.85-1.11, I(2) 0%] and a significant reduction of stroke/SEE in other regions including North America, Latin America and Asia-Pacific/other (RR 0.72, 95% CI 0.63-0.83, I(2) 33%). There was a similar reduction in risk of major bleeding in Europe (RR 0.82, 95% CI 0.73-0.92, I(2) 0%) and in other regions (RR 0.86, 95% CI 0.72-1.02, I(2) 78%). CONCLUSION: The DOAC did not provide additional benefit in reducing the risk of stroke/SEE compared with warfarin in European patients with AF, but were generally associated with a lower bleeding tendency than warfarin regardless of geographic region.

Overweight and obesity in young Turkish, Moroccan and Surinamese migrants of the second generation in the Netherlands.

OBJECTIVE: To examine differences in overweight and obesity of second-generation Turkish, Moroccan and Surinamese migrants v. first-generation migrants and the ethnic Dutch. We also studied the influence of sociodemographic factors on this association. DESIGN: Data were collected in 2008 in a cross-sectional postal and online health survey. SETTING: Four major Dutch cities. SUBJECTS: In the survey 42 686 residents aged 16 years and over participated. Data from Dutch (n 3615) and second/first-generation Surinamese (n 230/139), Turkish (n 203/241) and Moroccan (n 172/187) participants aged 16-34 years were analysed using logistic regression with overweight (BMI ≥ 25·0 kg/m²) and obesity (BMI ≥ 30·0 kg/m²) as dependent variables. BMI was calculated from self-reported body height and weight. Sociodemographic variables included sex, age, marital status, educational level, employment status and financial situation. RESULTS: After controlling for age, overweight (including obesity) was more prevalent in most second-generation migrant subgroups compared with the Dutch population, except for Moroccan men. Obesity rates among second-generation migrant men were similar to those among the Dutch. Second-generation migrant women were more often obese than Dutch women. Ethnic differences were partly explained by the lower educational level of second-generation migrants. Differences in overweight between second- and first-generation migrants were only found among Moroccan and Surinamese men. CONCLUSIONS: We did not find a converging trend for the overweight and obesity prevalence from second-generation migrants towards the Dutch host population. Therefore, preventive interventions should also focus on second-generation migrants to stop the obesity epidemic.

Associations of socioeconomic status indicators and migrant status with risk of a low vegetable and fruit consumption in children.

BACKGROUND: It is important to provide insight in potential target groups for interventions to reduce socioeconomic inequalities in children's vegetable/fruit consumption. In earlier studies often single indicators of socioeconomic status (SES) or migrant status have been used. However, SES is a multidimensional concept and different indicators may measure different SES dimensions. Our objective is to explore multiple associations of SES indicators and migrant status with risk of a low vegetable/fruit consumption in a large multi-ethnic and socioeconomically diverse sample of children. METHODS: We included 5,010 parents of 4- to 12-year-olds from a Dutch public health survey administered in 2018. Cross-sectional associations of parental education, material deprivation, perceived financial difficulties, neighbourhood socioeconomic status (NSES) and migrant status with low (≤4 days a week) vegetable and fruit consumption in children were assessed using multilevel multivariable logistic regression models. Results are displayed as odds ratios (OR) with 95% confidence intervals (CI). RESULTS: Of the 4- to 12-year-olds, 22.1% had a low vegetable consumption and 11.9% a low fruit consumption. Low (OR 2.51; 95%CI: 2.05, 3.07) and intermediate (OR 1.83; 95%CI: 1.54, 2.17) parental education, material deprivation (OR 1.45; 95%CI: 1.19, 1.76), low NSES (OR 1.28; 95%CI: 1.04, 1.58) and a non-Western migrant status (OR 1.94; 95%CI: 1.66, 2.26) were associated with a higher risk of a low vegetable consumption. Low (OR 1.68; 95%CI: 1.31, 2.17) and intermediate (OR 1.39; 95%CI: 1.12, 1.72) parental education and material deprivation (OR 1.63; 95%CI: 11.27, 2.08) were also associated with a higher risk of a low fruit consumption. CONCLUSION: Our findings indicate associations of multiple SES indicators and migrant status with a higher risk of a low vegetable/fruit consumption in children and thus help to identify potential target groups.

Pharmacotherapy for stroke prevention in nonvalvular atrial fibrillation: current strategies and future directions.

INTRODUCTION: Cardioembolic stroke, associated to nonvalvular atrial fibrillation (NVAF), accounts for approximately one in every four strokes. Cardioembolic stroke has a bad prognosis and is associated with a significant rate of recurrence. AREAS COVERED: This article reviews current pharmacotherapeutic options for prevention of stroke in NVAF, paying special attention to their use in particular clinical settings (e.g. cardioversion, catheter ablation). We also aim to review new drug candidates that have entered clinical studies in this indication. EXPERT OPINION: Oral anticoagulant therapy (OAT) remains the mainstay for ischemic stroke prophylaxis in NVAF in patients at risk. Several oral (asundexian, milvexian) and parenteral (abelacimab, osocimab, xisomab, IONIS-FXIRX, fesomersen) factor XIa inhibitors are under development. These new compounds appear to be associated with a low bleeding tendency and have the potential to complement current existing alternatives for anticoagulation. However, it is also of paramount importance to implement interventions to improve adherence to available anticoagulants, which is currently suboptimal. Non-anticoagulant drugs, such as colchicine, metformin and dronedarone, also being investigated to reduce the burden of NVAF and cardioembolic stroke. Additional clinical data are needed to more clearly define the role of these drugs for stroke prevention in NVAF.

Gadolinium-enhanced brain lesions in multiple sclerosis relapse.

OBJECTIVE: To study the clinico-radiological paradox in multiple sclerosis (MS) relapse by analyzing the number and location of gadolinium-enhanced (Gd+) lesions on brain MRI before methylprednisolone (MP) treatment. METHODS: We analyzed brain MRI from 90 relapsed MS patients in two Phase IV multicenter double-blind randomized clinical trials that showed the noninferiority of different routes and doses of MP administration. A 1.5- or 3-T brain MRI was performed at baseline before MP treatment and within 15 days of symptom onset. The number and location of Gd+ lesions were analyzed. Associations were studied using univariate analysis. RESULTS: Sixty-two percent of patients had at least 1 Gd+ brain lesion; the median number was 1 (interquartile range 0-4), and 41% of patients had 2 or more lesions. The most frequent location of Gd+ lesions was subcortical (41.4%). Gd+ brain lesions were found in 71.4% of patients with brainstem-cerebellum symptoms, 57.1% with spinal cord symptoms and 55.5% with optic neuritis (ON). Thirty percent of patients with brain symptoms did not have Gd+ lesions, and only 43.6% of patients had symptomatic Gd+ lesions. The univariate analysis showed a negative correlation between age and the number of Gd+ lesions (p=0.002). CONCLUSION: Most patients with relapse showed several Gd+ lesions on brain MRI, even when the clinical manifestation was outside of the brain. Our findings illustrate the clinico-radiological paradox in MS relapse and support the value of brain MRI in this scenario.

What makes hospitalized patients more vulnerable and increases their risk of experiencing an adverse event?

OBJECTIVE: To analyze the relationship between the appearance of adverse events (AEs) and both patient comorbidities and the use of medical devices. DESIGN: Retrospective medical records review study. SETTING: Twenty-four Spanish public hospitals. PARTICIPANTS: Clinical records of 5624 discharged patients. MAIN OUTCOME MEASURE: Incidence of AEs. RESULTS: Patients aged >65 have 2.4 times the risk of experiencing an AE compared with those aged <65. The presence of certain comorbidities and devices (neoplasia, chronic hepatic alteration, cardiac insufficiency, coronary disease, high blood pressure, urethral catheterization, catheterization of a vessel, tracheostomy or stay of >7 days) were associated with developing an AE during hospitalization. There is a trend effect if we consider the number of comorbidities and the number of devices used. Thus, the risk of an AE in subjects who present no comorbidities was 3.2%, which rose to 9.9% in those with one intrinsic risk factor, 16.7% in those with two and 29.3% in those with three or more. Similarly, subjects without extrinsic risk factor experienced an AE in 4.4% of cases, which rose to 9.6% when there was one risk factor, to 13.4% when there were two and to 33.0% when there were three or more risk factors. The effect of some of these pathologies and that associated with age disappeared on adjusting in line with other variables. CONCLUSIONS: The true risk resides in the number of exposures to potentially iatrogenic actions, rather than being intrinsic to age or the presence of certain comorbidities.

[Harmful algal blooms in Italy and their health effects in the population]. / Fioriture algali: effetti sulla salute della popolazione.

The authors discuss harmful algal bloom, a seasonal phenomenon that in recent years has become increasingly frequent along Italian coasts. A classification of algal bloom is given and algal toxins and their effects on human health are discussed. The authors then describe the algal bloom phenomenon observed in Italy from the 1960s to the present time. Finally they briefly describe Italian legislation on the subject matter and highlight its shortcomings.

Independent contributions of family and neighbourhood indicators of socioeconomic status and migrant status to risk of mental health problems in 4-12 year old children.

RATIONALE: A range of family and neighbourhood indicators of socioeconomic status and migrant status have been shown to be associated with risk of mental health l problems (MHP) in children. In this study we determined the independent contributions of these indicators. OBJECTIVES: The main objective is to examine independent associations of family and neighbourhood socioeconomic status indicators and migrant status with risk of MHP in children. METHODS: We analyzed data from an anonymous public health survey among 5010 parents/caretakers of children aged 4-12 years living in Rotterdam, The Netherlands, gathered in 2018. Outcome of interest was risk of MHP measured using the total difficulties score of the Strengths and Difficulties Questionnaire. Associations of parent-reported perceived financial difficulties, material deprivation (not being able to provide certain goods, or leisure, educational or cultural activities or care use for children due to financial restrictions), parental educational level, child's migrant status and neighbourhood socioeconomic status with risk of MHP and with the total difficulties score were assessed using multilevel multivariable logistic and linear regression models. RESULTS: In total, 473 (9.5%) children had a high risk of MHP. We observed independent associations of perceived financial difficulties, material deprivation and parental educational level with risk of MHP and with an increase in total difficulties score (P < 0.05). Migrant status and neighbourhood socioeconomic status were not independently associated with risk of MHP or a change in total difficulties score. CONCLUSIONS: Already in early life, perceived financial difficulties by parents, material deprivation reported by parents and lower parental education appeared to be independently associated with the risk of MHP in 4-12 year olds. Health professionals should be aware of the relatively higher risks in these subgroups and consider policies address this.

[Clinical characteristics of patients with stroke code activation not identified by the emergency medical service]. / Características clínicas de los pacientes con activación de código ictus no identificados por el servicio de emergencias médicas.

AIMS: To determine the sensitivity of stroke detection by emergency medical services (EMS) and to analyse the clinical characteristics of unidentified patients with suspected stroke. PATIENTS AND METHODS: Prospective register of patients with suspected stroke in our area (850,000 inhabitants) from 2011 to 2017. The population that notified the EMS was selected. Of this population, patients with and without stroke code activation by the EMS were compared (EMS+ versus EMS-). Demographics, time to progression, clinical characteristics of the episode and reperfusion therapy administered were recorded. RESULTS: Of a total of 5,497 patients with suspected stroke, 2,087 alerted the EMS: 1,611 (77%) EMS+ and 476 (33%) EMS-. The EMS- patients presented lower scores on the National Institute of Health Stroke Scale (8 vs. 11) and a greater frequency of clinical features of the vertebrobasilar territory (14.1% vs. 8.7%) and partial hemispheric clinical features (23.5% vs. 18.4%), especially in the left hemisphere (78.1% vs. 48.4%). Reperfusion treatment was administered in 29% of EMS+ and 23% of EMS-. The time from symptom onset to treatment was 42 minutes longer in the EMS group (175 versus 133 minutes). CONCLUSIONS: The sensitivity of EMS to detect stroke patients in our series is 77%. We have identified clinical features associated with lack of sensitivity, such as vertebrobasilar territory symptoms or isolated language disorder.

TITLE: Características clínicas de los pacientes con activación de código ictus no identificados por el servicio de emergencias médicas.Objetivos. Determinar la sensibilidad de detección de ictus por parte de los servicios de emergencias médicas (SEM) y analizar las características clínicas de los pacientes con sospecha de ictus no identificados. Pacientes y métodos. Registro prospectivo de pacientes con sospecha de ictus de nuestra área (850.000 habitantes) desde 2011 hasta 2017. Se seleccionó a la población que avisó al SEM. De ésta, se compararon los pacientes con y sin activación de código ictus por parte del SEM (SEM+ frente a SEM-). Se registraron los datos demográficos, el tiempo de evolución, las características clínicas del episodio y el tratamiento de reperfusión administrado. Resultados. De un total de 5.497 pacientes con sospecha de ictus, 2.087 alertaron al SEM: 1.611 (77%) SEM+ y 476 (33%) SEM-. Los pacientes SEM- presentaron menor puntuación en la National Institute of Health Stroke Scale (8 frente a 11) y mayor frecuencia de clínica de territorio vertebrobasilar (14,1% frente a 8,7%) y de clínica hemisférica parcial (23,5% frente a 18,4%), especialmente del hemisferio izquierdo (78,1% frente a 48,4%). Se administró tratamiento de reperfusión en el 29% de los SEM+ y en el 23% de los SEM-. El tiempo desde el inicio de los síntomas hasta el tratamiento fue 42 minutos más largo en el grupo de pacientes SEM- (175 frente a 133 minutos). Conclusiones. La sensibilidad del SEM para detectar pacientes con ictus en nuestra serie es del 77%. Hemos identificado características clínicas asociadas a la falta de sensibilidad, como los síntomas de territorio vertebrobasilar o el trastorno de lenguaje aislado.

Ethnic Differences in Fall Risk Among Community-Dwelling Older People in the Netherlands.

OBJECTIVE: This study measures the prevalence of falls and fear of falling among a population sample aged ≥65 years from different ethnic minorities living in the Netherlands, and examines whether ethnicity contributed to the differences in fall risk. METHOD: We analyzed data from 8,892 Dutch, Moroccan, Turkish, and Surinamese participants. Descriptive statistics and multiple regression analyses were conducted with falls and fear of falling as the dependent variable and ethnicity as the independent variable. RESULTS: Moroccan, Turkish, and Surinamese older adults had a significantly higher odds ratio (OR) for fear of falling than their Dutch counterparts (OR = 2.13, 95% confidence interval [CI] = [1.05, 4.31]; OR = 2.09, 95% CI = [1.07, 4.09]; and OR = 2.49, 95% CI = [1.53, 4.03], respectively). The association between ethnicity and falling disappeared after controlling for socio-demographic and health characteristics. DISCUSSION: Dutch minority older adults were at higher risk for fear of falling than their Dutch counterparts. The study underlines the need for targeting culture-sensitive interventions.

Gadolinium-enhanced brain lesions in multiple sclerosis relapse / Lesiones cerebrales captantes de gadolinio en el brote de los pacientes con esclerosis múltiple

Objective: To study the clinico-radiological paradox in multiple sclerosis (MS) relapse by analyzing the number and location of gadolinium-enhanced (Gd+) lesions on brain MRI before methylprednisolone (MP) treatment. Methods: We analyzed brain MRI from 90 relapsed MS patients in two Phase IV multicenter double-blind randomized clinical trials that showed the noninferiority of different routes and doses of MP administration. A 1.5- or 3-T brain MRI was performed at baseline before MP treatment and within 15 days of symptom onset. The number and location of Gd+ lesions were analyzed. Associations were studied using univariate analysis. Results: Sixty-two percent of patients had at least 1 Gd+ brain lesion; the median number was 1 (interquartile range 0–4), and 41% of patients had 2 or more lesions. The most frequent location of Gd+ lesions was subcortical (41.4%). Gd+ brain lesions were found in 71.4% of patients with brainstem-cerebellum symptoms, 57.1% with spinal cord symptoms and 55.5% with optic neuritis (ON). Thirty percent of patients with brain symptoms did not have Gd+ lesions, and only 43.6% of patients had symptomatic Gd+ lesions. The univariate analysis showed a negative correlation between age and the number of Gd+ lesions (p = 0.002). Conclusion: Most patients with relapse showed several Gd+ lesions on brain MRI, even when the clinical manifestation was outside of the brain. Our findings illustrate the clinico-radiological paradox in MS relapse and support the value of brain MRI in this scenario. (AU)

Objetivo: Estudiar la paradoja clínico-radiológica en el brote de la esclerosis múltiple (EM) mediante el análisis de lesiones captantes de gadolinio (Gd+) en la RM cerebral antes del tratamiento con metilprednisolona (MP). Métodos: Analizamos la RM cerebral basal de 90 pacientes con EM en brote de 2 ensayos clínicos aleatorizados multicéntricos fase IV que demostraron la no inferioridad de diferentes vías y dosis de MP, realizadas antes del tratamiento con MP y en los 15 días siguientes a la aparición de los síntomas. Se analizaron el número y la localización de las lesiones Gd+. Se estudiaron las asociaciones mediante análisis univariado. Resultados: El 62% de los pacientes tenía al menos una lesión Gd+ cerebral y el 41% de los pacientes tenía 2 o más lesiones. La localización más frecuente fue la subcortical (41,4%). Se encontraron lesiones Gd+ cerebrales en el 71,4% de los pacientes con síntomas de tronco cerebral o cerebelo, en el 57,1% con síntomas medulares y en el 55,5% con neuritis óptica. El 30% de los pacientes con síntomas cerebrales no tenían lesiones Gd+ y sólo el 4,.6% de los pacientes tenían lesiones Gd+ sintomáticas. El análisis univariante mostró una correlación negativa entre la edad y el número de lesiones Gd+ (p = 0,002). Conclusiones: La mayoría de los pacientes en brote mostraron varias lesiones Gd+ en la RM cerebral, incluso cuando la manifestación clínica fue medular u óptica. Nuestros hallazgos ilustran la paradoja clínico-radiológica en el brote de la EM y apoyan el valor de la RM cerebral en este escenario. (AU)

Case Fatality Rates of Recurrent Thromboembolism and Bleeding in Patients Receiving Direct Oral Anticoagulants for the Initial and Extended Treatment of Venous Thromboembolism: A Systematic Review.

BACKGROUND: In patients with venous thromboembolism (VTE), the study of the case fatality rate (CFR) of VTE recurrences and bleeding complications may be of help to balance the risks and benefits of anticoagulant therapy. OBJECTIVE: To investigate the CFR with the direct oral anticoagulants (DOACs; dabigatran, rivaroxaban, apixaban, and edoxaban) in patients with VTE. METHODS: We conducted a systematic review and meta-analysis of randomized clinical trials testing the DOACs versus standard initial treatment of VTE (parenteral anticoagulant for ≥5 days plus vitamin K antagonists [VKAs] for ≥3 months) and DOACs versus placebo or VKA for extended treatment. Two investigators independently extracted the data. A random effects meta-analysis was conducted using StatsDirect software. RESULTS: Overall, 10 trials in 35 029 patients were included. During initial treatment, the rate of recurrent VTE per 100 patient-years (%/yr) and CFR (%) was similar in patients receiving DOACs or standard therapy (4.1%/yr vs 4.4%/yr; P = .21 and 16% vs 13%; P = .61, respectively). However, major bleeding (1.8%/yr vs 3.1%/yr; P = .003), fatal bleeding (0.1%/yr vs 0.3%/yr; P = .02), and CFR (6% vs 10%; P = .18) were lower with DOACs than with standard therapy. During extended treatment, both all-cause mortality and recurrent VTE per 100 patient-years were lower with DOACs than with placebo (0.6%/yr vs 1.1%/yr; P = .01 and 1.9%/yr vs 10.9%/yr; P < .0001, respectively), but there were no statistical differences between treatments on CFR of VTE recurrences (P = .17). No fatal bleeding events were reported during extended treatment. CONCLUSION: The use of DOACs was associated with fewer major and fatal bleedings and corresponding CFR than standard initial treatment of VTE, and fewer recurrent VTEs and mortality than placebo during extended therapy, although the CFR of recurrent VTE was not reduced.

Ketomethylene and (cyanomethylene)amino pseudopeptide analogues of the C-terminal hexapeptide of neurotensin.

A series of pseudopeptide analogues of the C-terminal hexapeptide of neurotensin (NT8-13), namely [Tyr11 psi[COCH2]Phe12]-, [Ile12 psi[COCH2]Phe13]-, and [Tyr11 psi[CH(CN)NH]Ile12]NT8-13 with different stereochemistries, has been synthesized and evaluated for its potency in displacing labeled NT from rat cortex membranes. Ketomethylene pseudohexapeptides were prepared from the corresponding Boc-protected ketomethylene dipeptide derivatives, previously formed, using different solid phase synthesis (SPS) conditions, while (cyanomethylene)amino analogues were directly prepared by SPS using Fmoc strategy. H-Arg-Arg-Pro-Tyr psi[COCH2]-Phe-Leu-OH was nearly as potent as NT8-13 and [Phe12]NT8-13 in binding to the receptor. Comparison of the affinities for the pseudohexapeptides, here reported, with those of the psi-[CH2NH] analogues indicates the importance of the CO group in the amide or surrogate linkage at 11-12 and 12-13 positions in the receptor binding process.

Popliteal artery entrapment syndrome.

Three cases of popliteal artery entrapment syndrome, one of them bilateral, are presented with a review of the literature, with special reference to the embryological development of the popliteal space and the diagnostic and therapeutic problems presented by this syndrome.

[Tumor markers in liver metastases of colorectal carcinoma]. / Marcadores tumorales en metástasis hepáticas del carcinoma colorrectal.

Colorectal cancer is a potentially curable tumour when diagnosed in the early stages. In order to improve the results obtained up to now, we propose application of a diagnostic program among patients who undergo curative resection for colorectal adenocarcinoma, which would consist of using a panel of tumor markers, in combination with endoscopic, histologic and ultrasonographic diagnostic methods. For this study we studied 105 patients, divided into two groups: A) Group 1: 30 control patients. B) Group 2: 75 patients diagnosed as having colorectal cancer. We performed the preoperative determination of a series of tumor markers (CEA, CA 19.9, GGT and PHI), endoscopy/biopsy and hepatic ultrasonography on these patients. Our results suggest that the design of the preoperative diagnostic program makes early detection of hepatic metastases possible. The tumor marker panel combination provided a visible increase in sensitivity for detecting hepatic metastases.

Direct oral anticoagulants in the treatment of venous thromboembolism, with a focus on patients with pulmonary embolism: an evidence-based review.

Pulmonary embolism (PE) is a relatively common cardiovascular emergency. PE and deep vein thrombosis (DVT) are considered expressions of the same disease, termed as venous thromboembolism (VTE). In the present review, we describe and meta-analyze the efficacy and safety data available with the direct oral anticoagulants (DOAC; dabigatran, rivaroxaban, apixaban, edoxaban) in clinical trials testing these new compounds in the acute/long-term and extended therapy of VTE, providing subgroup analyses in patients with index PE. We analyzed ten studies in 35,019 randomized patients. A total of 14,364 patients (41%) had index PE. In the acute/long-term treatment of VTE, the DOAC showed comparable efficacy in preventing recurrent VTE to standard treatment in patients with index PE (risk ratio [RR]: 0.88; 95% confidence interval [CI]: 0.70-1.11) and index DVT (RR: 0.93; 95% CI: 0.75-1.16) (P for subgroup differences =0.76). VTE recurrence depending on PE anatomical extension and presence/absence of right ventricular dysfunction was only reported in two trials, with results being consistent with those obtained in the overall study populations. In the single trial comparing extended therapy of VTE with DOAC versus warfarin, the point estimate for recurrent VTE tended to disfavor the DOAC in patients with index PE (RR: 2.05; 95% CI: 0.83-5.03) and in patients with index DVT (RR: 1.11; 95% CI: 0.49-2.50) (P for subgroup differences =0.32). In trials that compared DOAC versus placebo for extended therapy, the reduction in recurrent VTE was consistent in patients with PE (RR: 0.15; 95% CI: 0.01-1.82) and in patients with DVT (RR: 0.25; 95% CI: 0.10-0.61) (P for subgroup differences =0.71). The DOAC were associated with a consistently lower risk of clinically relevant bleeding (CRB) than standard treatment of acute VTE and higher risk of CRB than placebo for extended therapy of VTE regardless of index event. In summary, the DOAC were as effective as, and safer than, standard treatment of (hemodynamically stable) PE. Their efficacy in preventing recurrent VTE seemed consistent regardless of anatomical extension of PE (extensive, intermediate, or limit) or presence/absence of right ventricular dysfunction although the data are limited. For extended therapy, the DOAC were more effective than placebo in preventing recurrent VTE but were associated with an increase in CRB regardless of index event.

Specific antidotes in development for reversal of novel anticoagulants: a review.

In the last decade, several direct oral anticoagulants (DOAC; dabigatran, rivaroxaban, apixaban, edoxaban) have been marketed for prophylaxis and/or treatment of thromboembolism without having specific antidotes available for their reversal. Current management of bleeding associated to DOAC includes the removal of all antithrombotic medications and supportive care. Non-specific procoagulant agents (prothrombin complex concentrates and activated factor VIIa) have been used in case of serious bleeding. Currently, some specific antidotes for the DOAC are under development. Idarucizumab (BI 655075; Boehringer Ingelheim) is a fragment of an antibody (Fab), which is a specific antidote to the oral direct thrombin inhibitor dabigatran. Andexanet alfa (r-Antidote, PRT064445; Portola Pharmaceuticals) is a truncated form of enzymatically inactive factor Xa, which binds and reverses the anticoagulant action of the factor Xa inhibitors (e.g.: rivaroxaban, apixaban and edoxaban). Aripazine (PER-977, ciraparantag; Perosphere Inc.) is a synthetic small molecule (~500 Da) that reverses oral dabigatran, apixaban, rivaroxaban, as well as subcutaneous fondaparinux and LMWH in vivo. These antidotes could provide an alternative for management of life-threatening bleeding events occurring with the above-mentioned anticoagulants. In addition, the specific antidote anivamersen (RB007; Regado Biosciences Inc.) is an RNA aptamer in clinical development to reverse the anticoagulant effect of the parenteral factor IXa inhibitor pegnivacogin, which is also in development. This anticoagulant-antidote pair may provide an alternative in situations in which a fast onset and offset of anticoagulation is needed, like in patients undergoing cardiac surgery with extracorporeal circulation, as an alternative to the heparin/protamine pair. This patent review includes a description of the pharmacological characteristics of the novel specific antidotes, the available results from completed non-clinical and clinical studies and the description of ongoing clinical trials with the new compounds.

Direct oral anticoagulants in the treatment of acute venous thromboembolism: a systematic review and meta-analysis.

INTRODUCTION: Acute venous thromboembolism (VTE) is a common disease associated to significant morbidity and mortality. MATERIALS AND METHODS: We systematically reviewed and meta-analysed clinical outcomes with direct oral anticoagulants (DOAC: dabigatran, rivaroxaban, apixaban or edoxaban) for treatment of acute VTE. We used MEDLINE and CENTRAL, clinical trials registers, conference proceedings, and websites of regulatory agencies to identify randomised clinical trials of DOAC compared with conventional treatment [parenteral anticoagulant followed by a vitamin K antagonist (VKA)] for acute VTE. Two investigators independently extracted data. Relative risk of recurrent VTE, bleeding events, deaths and a net clinical endpoint (composite of recurrent VTE, major bleeding, and death) were estimated using a random effect meta-analysis (RevMan software). RESULTS: Six trials including 27,127 patients were selected. The risk of recurrent VTE was similar with the DOAC and standard treatment (relative risk 0.91, 95% confidence interval 0.79 to 1.06). The DOAC reduced the risk of major bleeding in comparison with standard treatment (0.62, 0.45 to 0.85) (absolute risk difference, -0.6%; 95% confidence interval -1.0% to -0.3%), but there was heterogeneity across trials in the relative risk of bleeding. No between treatment differences were found in the relative risk of all-cause mortality (0.98, 0.84 to 1.14). The DOAC and conventional treatment differed on the net clinical endpoint (0.85, 0.75 to 0.97). Subgroup analyses in relevant subgroups (index pulmonary embolism, heparin lead-in, age, gender, renal function, presence of cancer), as well as sensitivity analyses, were consistent with the main analysis. CONCLUSIONS: The DOAC seem as effective as, and probably safer than standard treatment of acute VTE. The relative efficacy and safety of the DOAC was consistent across a wide range of patients.