Validation of the International Classification of Functioning, Disability, and Health (ICF) core set for post-acute musculoskeletal conditions in a primary care physiotherapy setting from the perspective of patients using focus groups.

PURPOSE: To validate the comprehensive ICF core set for post-acute musculoskeletal conditions from the perspective of patients in a primary care physiotherapy setting. MATERIALS AND METHODS: A qualitative study was conducted with patients suffering from musculoskeletal problems. A phenomenological approach based on focus groups was used to identify the most relevant aspects related to physical therapy care in their condition. The data were analyzed using a meaning condensation procedure, identifying relevant themes and concepts. The identified concepts were linked to the ICF and compared to the ICF core set for post-acute musculoskeletal conditions. RESULTS: Forty-three patients were included in eight focus groups. A total of 1281 relevant concepts were extracted and related to 156 ICF second-level entities. Entities in the ICF core set for post-acute musculoskeletal conditions were 95.7% confirmed. Eighty-nine additional second-level ICF entities were identified. CONCLUSIONS: Entities in the ICF core set for post-acute musculoskeletal conditions are relevant to patients seen in primary care physical therapy units. However, there are areas of functioning related to community health care not covered by this ICF-based tool.IMPLICATIONS OF REHABILITATIONAn ICF-based framework is feasible for the assessment of musculoskeletal conditions.Post-acute musculoskeletal ICF core set was confirmed in patient focus groups.Additional ICF categories emerged for a primary care physical therapy setting.Community features of functioning could be addressed by a tailored ICF core set.

Late gadolinium enhancement distribution patterns in non-ischaemic dilated cardiomyopathy: genotype-phenotype correlation.

AIMS: Late gadolinium enhancement (LGE) is frequently found in patients with dilated cardiomyopathy (DCM); there is little information about its frequency and distribution pattern according to the underlying genetic substrate. We sought to describe LGE patterns according to genotypes and to analyse the risk of major ventricular arrhythmias (MVA) according to patterns. METHODS AND RESULTS: Cardiac magnetic resonance findings and LGE distribution according to genetics were performed in a cohort of 600 DCM patients followed at 20 Spanish centres. After exclusion of individuals with multiple causative gene variants or with variants in infrequent DCM-causing genes, 577 patients (34% females, mean age 53.5 years, left ventricular ejection fraction 36.9 ± 13.9%) conformed to the final cohort. A causative genetic variant was identified in 219 (38%) patients, and 147 (25.5%) had LGE. Significant differences were found comparing LGE patterns between genes (P < 0.001). LGE was absent or rare in patients with variants in TNNT2, RBM20, and MYH7 (0, 5, and 20%, respectively). Patients with variants in DMD, DSP, and FLNC showed a predominance of LGE subepicardial patterns (50, 41, and 18%, respectively), whereas patients with variants in TTN, BAG3, LMNA, and MYBPC3 showed unspecific LGE patterns. The genetic yield differed according to LGE patterns. Patients with subepicardial, lineal midwall, transmural, and right ventricular insertion points or with combinations of LGE patterns showed an increased risk of MVA compared with patients without LGE. CONCLUSION: LGE patterns in DCM have a specific distribution according to the affected gene. Certain LGE patterns are associated with an increased risk of MVA and with an increased yield of genetic testing.

[Sociodemographic comparative between the periods 2007-2009 and 2015-2019 of the Gender Identity Treatment Unit of Asturias]. / Estudio sociodemográfico comparativo de los períodos 2007-2009 y 2015-2019 de la Unidad de Tratamiento de Identidad de Género del Principado de Asturias.

BACKGROUND AND OBJECTIVE: The high demand of assistance made by trans people in recent years has directed the focus of research towards the study of their clinical and sociodemographic aspects. The objective of this work was to compare and analyze some sociodemographic variables in trans people in two periods: the period when the unit began to operate and the most recent period. MATERIALS AND METHOD: A sample of 131 users who attended the Gender Identity Treatment Unit of the Principality of Asturias (UTIGPA) between 2015-2019 was compared with a sample of 33 who attended between 2007-2009. Data were extracted from medical records. RESULTS: Regarding 2007-2009, in 2015-2019 the ratio is inverted in favor of Trans Men (TM). Users of both genders request consultation at an earlier age (specially TM), come less from abroad, achieve higher educational and work qualifications, are less unemployed and request more name changes. And, although Trans Women (TW) continue to be those who are mostly engaged in prostitution and self-administration of hormones, in the most recent period they report it less and, furthermore, they live more accompanied tan in the past. CONCLUSIONS: Changes are observed in the sociodemographic variables of UTIGPA users between 2007-2009 and 2015-2019, in the direction of a greater inclusion. However, the sociodemographic conditions of the TW are still at a disadvantage in comparison to those of the TM.

[Gender dysphoria in trans minors: Ecological niche]. / La disforia de género en menores trans: nicho ecológico.

BACKGROUND AND OBJECTIVE: The objective of the present study is to investigate the contextual characteristics of the onset of gender dysphoria (GD) in trans minors. MATERIALS AND METHOD: All minors who requested consultation in the Gender Identity Treatment Unit from March 2007 to June 2019 participated. Clinical histories were reviewed to obtain the information. Confidentiality was guaranteed. RESULTS: Sixty-four minors required care, 39.1% were trans women (TW) and 60.9% trans men (TM). The age range was between 6-17 years, with a mean of 14.98. Seventy-five percent of the trans minors located the onset of DG in childhood and 25% in adolescence. Parental reaction was suspicious in 55.6% of cases and surprise in 36.5%; 55.6% presented significant psychological distress before going to the unit. Family support was present in 57.1%. The role of social networks and the Internet was relevant for 39.7% of the sample. Of the minors, 44.4% had membership or contact with peer groups or LGTBIQ associations. Results were analysed according to sense of gender. CONCLUSIONS: Minors continue to require care in the units, especially TW. Although GD onset in both groups is mainly in childhood, in adolescence it is more frequent in TM. Trans minors are born, develop and build their identity in a specific context, which is in interaction.

Association of Genetic Variants With Outcomes in Patients With Nonischemic Dilated Cardiomyopathy.

BACKGROUND: The clinical relevance of genetic variants in nonischemic dilated cardiomyopathy (DCM) is unsettled. OBJECTIVES: The study sought to assess the prognostic impact of disease-causing genetic variants in DCM. METHODS: Baseline and longitudinal clinical data from 1,005 genotyped DCM probands were retrospectively collected at 20 centers. A total of 372 (37%) patients had pathogenic or likely pathogenic variants (genotype positive) and 633 (63%) were genotype negative. The primary endpoint was a composite of major adverse cardiovascular events. Secondary endpoints were end-stage heart failure (ESHF), malignant ventricular arrhythmia (MVA), and left ventricular reverse remodeling (LVRR). RESULTS: After a median follow-up of 4.04 years (interquartile range: 1.70-7.50 years), the primary endpoint had occurred in 118 (31.7%) patients in the genotype-positive group and in 125 (19.8%) patients in the genotype-negative group (hazard ratio [HR]: 1.51; 95% confidence interval [CI]: 1.17-1.94; P = 0.001). ESHF occurred in 60 (16.1%) genotype-positive patients and in 55 (8.7%) genotype-negative patients (HR: 1.67; 95% CI: 1.16-2.41; P = 0.006). MVA occurred in 73 (19.6%) genotype-positive patients and in 77 (12.2%) genotype-negative patients (HR: 1.50; 95% CI: 1.09-2.07; P = 0.013). LVRR occurred in 39.6% in the genotype-positive group and in 46.2% in the genotype-negative group (P = 0.047). Among individuals with baseline left ventricular ejection fraction ≤35%, genotype-positive patients exhibited more major adverse cardiovascular events, ESHF, and MVA than their genotype-negative peers (all P < 0.02). LVRR and clinical outcomes varied depending on the underlying affected gene. CONCLUSIONS: In this study, DCM patients with pathogenic or likely pathogenic variants had worse prognosis than genotype-negative individuals. Clinical course differed depending on the underlying affected gene.

Founder mutation in myosin-binding protein C with an early onset and a high penetrance in males.

OBJECTIVE: One of the challenges in hypertrophic cardiomyopathy (HCM) is to determine the pathogenicity of genetic variants and to establish genotype/phenotype correlations. This study aimed to: (1) demonstrate that MYBPC3 c.2149-1G>A is a founder pathogenic variant, (2) describe the phenotype and clinical characteristics of mutation carriers and (3) compare these patients with those with the most frequent pathogenic HCM variants: MYBPC3 p.Arg502Trp/Gln. METHODS: We reviewed genetic tests performed in HCM probands at our institution. We carried out transcript analyses to demonstrate the splicing effect, and haplotype analyses to support the founder effect of MYBPC3 c.2149-1G>A. Carriers with this mutation were compared with those from MYBPC3 p.Arg502Trp/Gln in terms of presentation features, imaging and outcomes. RESULTS: MYBPC3 c.2149-1G>A was identified in 8 of 570 probands and 25 relatives. Penetrance was age and sex dependent, 50.0% of the carriers over age 36 years and 75.0% of the carriers over 40 years showing HCM. Penetrance was significantly higher in males: in carriers older than 30 years old, 100.0% of males vs 50.0% of females had a HCM phenotype (p=0.01). Males were also younger at diagnosis (32±13 vs 53±10 years old, p<0.001). MYBPC3 c.2149-1G>A resulted in an abnormal transcript that led to haploinsufficiency and was segregated in two haplotypes. However, both came from one founder haplotype. Affected carriers showed a better functional class and higher left ventricular ejection fraction (LVEF) than patients with MYBPC3 p.Arg502Trp/Gln (p<0.05 for both). Nevertheless, the rate of major adverse outcomes was similar between the two groups. CONCLUSIONS: MYBPC3 c.2149-1G>A splicing variant is a founder mutation. Affected males show an early onset of HCM and with higher penetrance than women. Carriers show better functional class and higher LVEF than MYBPC3 p.Arg502Trp/Gln carriers, but a similar rate of major adverse outcomes.

Meta-Analysis of Reversal Agents for Severe Bleeding Associated With Direct Oral Anticoagulants.

BACKGROUND: Direct oral anticoagulants (DOACs) have shown a positive benefit-risk balance in both clinical trials and real-world data, but approximately 2% to 3.5% of patients experience major bleeding annually. Many of these patients require hospitalization, and the administration of reversal agents may be required to control bleeding. OBJECTIVES: The aim of this study was to investigate clinical outcomes associated with the use of 4-factor prothrombin complex concentrates, idarucizumab, or andexanet for reversal of severe DOAC-associated bleeding. METHODS: The investigators systematically searched for studies of reversal agents for the treatment of severe bleeding associated with DOAC. Mortality rates, thromboembolic events, and hemostatic efficacy were meta-analyzed using a random effects model. RESULTS: The investigators evaluated 60 studies in 4,735 patients with severe DOAC-related bleeding who were treated with 4-factor prothrombin complex concentrates (n = 2,688), idarucizumab (n = 1,111), or andexanet (n = 936). The mortality rate was 17.7% (95% confidence interval [CI]: 15.1% to 20.4%), and it was higher in patients with intracranial bleedings (20.2%) than in patients with extracranial hemorrhages (15.4%). The thromboembolism rate was 4.6% (95% CI: 3.3% to 6.0%), being particularly high with andexanet (10.7%; 95% CI: 6.5% to 15.7%). The effective hemostasis rate was 78.5% (95% CI: 75.1% to 81.8%) and was similar regardless of the reversal agent considered. The rebleeding rate was 13.2% (95% CI: 5.5% to 23.1%) and 78% of rebleeds occurred after resumption of anticoagulation. The risk of death was markedly and significantly associated with failure to achieve effective hemostasis (relative risk: 3.63; 95% CI: 2.56 to 5.16). The results were robust regardless of the type of study or the hemostatic scale used. CONCLUSIONS: The risk of death after severe DOAC-related bleeding remains significant despite a high rate of effective hemostasis with reversal agents. Failure to achieve effective hemostasis strongly correlated with a fatal outcome. Thromboembolism rates are particularly high with andexanet. Comparative clinical trials are needed.

[Sex/gender ratio of adolescents with gender dysphoria of the Gender Identity Treatment Unit of Asturias]. / Ratio sexo/género de los adolescentes con disforia de género de la Unidad de Tratamiento de Identidad de Género de Asturias.

BACKGROUND AND OBJECTIVE: Demand from minors with complaints of gender dysphoria has increased in recent years. This increase has been more pronounced in adolescent trans men in some international research studies. The first objective of this research study was to determine the sex/gender ratio of minors requesting a consultation in the Gender Identity Treatment Unit of the Principality of Asturias (UTIGPA) and presenting complaints of gender dysphoria. The second objective was to analyse the relationship of the sex/gender ratio with the age variable at which they requested the first consultation and the year in which they requested it. MATERIALS AND METHOD: The sample consisted of 42 children under 18, attended between January 2016 and January 2019. The medical records were then reviewed to obtain information. Descriptive statistics were analysed with the collected data. RESULTS: The sex / gender ratio over the period was 2/1 in favour of trans men. The average age at the request for consultation was 15.02 years (SD=1.84), with a range of 6 to 17 years. A higher percentage of applications was recorded (35.7%) in 2018, mostly made by trans men (93.3%). CONCLUSIONS: There was an inversion of the sex/gender ratio, a favour of trans men, over the last 3years, and an increase in the number of applications by adolescent trans men, coinciding with several international investigations.

Analysis of porcine IGF2 gene expression in adipose tissue and its effect on fatty acid composition.

IGF2:g.3072G>A polymorphism has been described as the causal mutation of a maternally imprinted QTL for muscle growth and fat deposition in pigs. The objective of the current work was to study the association between the IGF2:g.3072G>A polymorphism and the IGF2 gene expression and its effect on fatty acid composition in adipose tissue in different pig genetic backgrounds. A cis-eQTL region associated with the IGF2 mRNA expression in adipose tissue was identified in an eGWAS with 355 animals. The IGF2 gene was located in this genomic interval and IGF2g.3072G>A was the most significant SNP, explaining a 25% of the gene expression variance. Significant associations between IGF2:g.3072G>A polymorphism and oleic (C18:1(n-9); p-value = 4.18x10-07), hexadecanoic (C16:1(n-9); p-value = 4.04x10-07), linoleic (C18:2(n-6); p-value = 6.44x10-09), α-linoleic (C18:3(n-3); p-value = 3.30x10-06), arachidonic (C20:4(n-6); p-value = 9.82x10-08) FAs and the MUFA/PUFA ratio (p-value = 2.51x10-9) measured in backfat were identified. Animals carrying the A allele showed an increase in IGF2 gene expression and higher PUFA and lower MUFA content. However, in additional studies was observed that there could be other proximal genetic variants affecting FA composition in adipose tissue. Finally, no differences in the IGF2 gene expression in adipose tissue were found between heterozygous animals classified according to the IGF2:g.3072G>A allele inherited from the father (APGM or AMGP). However, pyrosequencing analysis revealed that there is imprinting of the IGF2 gene in muscle and adipose tissues, with stronger differences among the paternally and maternally inherited alleles in muscle. Our results suggested that IGF2:g.3072G>A polymorphism plays an important role in the regulation of IGF2 gene expression and can be involved in the fatty acid composition in adipose tissue. In both cases, further studies are still needed to deepen the mechanism of regulation of IGF2 gene expression in adipose tissue and the IGF2 role in FA composition.

Causes of Death in Patients with Venous Thromboembolism Anticoagulated with Direct Oral Anticoagulants: A Systematic Review and Meta-Analysis.

Death is more frequent than nonfatal recurrent venous thromboembolism (VTE) and major bleeding after acute VTE. The analysis of the causes of death is fundamental to explore new strategies to reduce mortality rates in these patients. The authors performed a meta-analysis to analyze mortality and independently adjudicated causes of death in anticoagulated patients due to VTE, and to evaluate potential differences between different anticoagulant schemes. They searched MEDLINE and CENTRAL, from January 1, 2000, to January 31, 2017, and performed additional searches in Web sites of regulatory agencies, clinical trial registers, and conference proceedings. Two investigators independently selected studies and extracted the data. Study quality was assessed with the Cochrane Collaboration's tool for assessing the risk of bias in randomized studies. Seven prospective randomized trials in 29,844 patients (22,025 patient-year follow-up) were included, comparing dabigatran, rivaroxaban, apixaban, and edoxaban with the standard anticoagulant treatment of VTE. A total of 718 patients died during the follow-up (3.4% per year; 95% confidence interval [CI]: 2.3-4.8). The most frequent causes of death were cancer (42%), followed by VTE (20%), infections (13%), hemorrhage (6%), heart disease (4%), and stroke (2%). There were no differences in the overall survival and causes of death according to the anticoagulant type. Concomitant active cancer during the study was significantly associated with death (odds ratio: 15.2; 95% CI: 9.2-25.1). Cancer is the leading cause of death in contemporary VTE trials. Interventions beyond anticoagulation, particularly in patients with active cancer, are needed.

Caso clínico: embarazo ectópico cervical, presentación de un caso clínico / Clinical case: cervical ectopic pregnancy, presentation of a clinical case

RESUMEN Antecedentes: El embarazo cervical es una forma rara del embarazo ectópico y representa < 1% de todos los embarazos ectópicos. Objetivo: Se presenta el caso de un embarazo ectópico cervical. Se realiza una revisión literaria sobre las diferentes opciones de manejo y tratamiento. Caso clínico: Mujer de 32 años en la semana 7+4 de embarazo en la que se objetiva un saco gestacional ístmico vascularizado, que ofrece dudas diagnósticas. Se establece el diagnóstico de embarazo ectópico cervical y se realiza un cerclaje por metrorragia. Conclusión: El embarazo ectópico cervical sigue siendo un reto importante en el campo del embarazo. El éxito del tratamiento conservador depende principalmente del diagnóstico precoz, lo que puede reducir las posibilidades de hemorragia grave y de histerectomía.

ABSTRACT Background: Cervical pregnancy is a rare type of ectopic pregnancy and it represents <1% of all ectopic pregnancies. Objetive: The case of a cervical ectopic pregnancy is presented. A literary review is carried out on the different management and treatment options. Case report: A 32-year-old woman in week 7 + 4 of pregnancy in which is objetived a vascularized isthmic gestational sac, which ofeers diagnostic doubt. The diagnosis of ectopic cervical pregnancy is established and cercaclage is performed by metrorrhagia. Conclusion: Cervical ectopic pregnancy remains a major challenge in the field of early pregnancy. The success of conservative treatment depends primarily on early diagnosis, which may reduce the chances of severe bleeding and require a hysterectomy.

Causes of Death in Anticoagulated Patients With Atrial Fibrillation.

BACKGROUND: Oral anticoagulation reduces the risk of mortality in atrial fibrillation (AF), but examination of the causes of death is essential to design new strategies to further reduce the high mortality rates observed in this population. OBJECTIVES: The authors sought to analyze and compare causes of death in patients receiving direct oral anticoagulants (DOAC) or warfarin for prevention of stroke and systemic embolism (SE) in AF. METHODS: The authors systematically searched for randomized trials of DOAC versus warfarin for prevention of stroke/SE in AF. The main outcome was mortality and independently adjudicated specific causes of death. The authors used the random effects model of meta-analysis to combine the studies. RESULTS: 71,683 patients from 4 trials were included (134,046 patient-years of follow-up). A total of 6,206 patients (9%) died during follow-up. Adjusted mortality rate was 4.72%/year (95% confidence interval [CI]: 4.19 to 5.28). Cardiac deaths accounted for 46% of all deaths, whereas nonhemorrhagic stroke/SE and hemorrhage-related deaths represented 5.7% and 5.6% of the total mortality, respectively. Compared with patients who were alive, those who died had more frequent history of heart failure (odds ratio [OR]: 1.75; 95% CI: 1.25 to 2.44), permanent/persistent AF (OR: 1.38; 95% CI: 1.25 to 1.52) and diabetes (OR: 1.37; 95% CI: 1.11 to 1.68); were more frequently male (OR: 1.24; 95% CI: 1.13 to 1.37) and older (mean difference 3.2 years; 95% CI: 1.6 to 4.8); and had a lower creatinine clearance (-9.9 ml/min; 95% CI: -11.3 to -8.4). There was a small, but significant, reduction in all-cause mortality with the DOAC versus warfarin (difference -0.42%/year; 95% CI: -0.66 to -0.18), mainly driven by a reduction in fatal bleedings. CONCLUSIONS: In contemporary AF trials, most deaths were cardiac-related, whereas stroke and bleeding represented only a small subset of deaths. Interventions beyond anticoagulation are needed to further reduce mortality in AF.

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.

Comparative Analysis of Muscle Transcriptome between Pig Genotypes Identifies Genes and Regulatory Mechanisms Associated to Growth, Fatness and Metabolism.

Iberian ham production includes both purebred (IB) and Duroc-crossbred (IBxDU) Iberian pigs, which show important differences in meat quality and production traits, such as muscle growth and fatness. This experiment was conducted to investigate gene expression differences, transcriptional regulation and genetic polymorphisms that could be associated with the observed phenotypic differences between IB and IBxDU pigs. Nine IB and 10 IBxDU pigs were slaughtered at birth. Morphometric measures and blood samples were obtained and samples from Biceps femoris muscle were employed for compositional and transcriptome analysis by RNA-Seq technology. Phenotypic differences were evident at this early age, including greater body size and weight in IBxDU and greater Biceps femoris intramuscular fat and plasma cholesterol content in IB newborns. We detected 149 differentially expressed genes between IB and IBxDU neonates (p < 0.01 and Fold-Change > 1. 5). Several were related to adipose and muscle tissues development (DLK1, FGF21 or UBC). The functional interpretation of the transcriptomic differences revealed enrichment of functions and pathways related to lipid metabolism in IB and to cellular and muscle growth in IBxDU pigs. Protein catabolism, cholesterol biosynthesis and immune system were functions enriched in both genotypes. We identified transcription factors potentially affecting the observed gene expression differences. Some of them have known functions on adipogenesis (CEBPA, EGRs), lipid metabolism (PPARGC1B) and myogenesis (FOXOs, MEF2D, MYOD1), which suggest a key role in the meat quality differences existing between IB and IBxDU hams. We also identified several polymorphisms showing differential segregation between IB and IBxDU pigs. Among them, non-synonymous variants were detected in several transcription factors as PPARGC1B and TRIM63 genes, which could be associated to altered gene function. Taken together, these results provide information about candidate genes, metabolic pathways and genetic polymorphisms potentially involved in phenotypic differences between IB and IBxDU pigs associated to meat quality and production traits.

Direct-acting oral anticoagulants: pharmacology, indications, management, and future perspectives.

In recent years, several direct-acting oral anticoagulants (DOAC) have become available for use in Europe and other regions in indications related to prophylaxis and treatment of venous and arterial thromboembolism. They include the oral direct thrombin inhibitor dabigatran etexilate (Pradaxa, Boehringer Ingelheim) and the oral direct FXa inhibitors rivaroxaban (Xarelto, Bayer HealthCare), apixaban (Eliquis, Bristol-Myers Squibb), and edoxaban (Lixiana/Savaysa, Daiichi-Sankyo). The new compounds have a predictable dose response and few drug-drug interactions (unlike vitamin k antagonists), and they do not require parenteral administration (unlike heparins). However, they accumulate in patients with renal impairment, lack widely available monitoring tests for measuring its anticoagulant activity, and no specific antidotes for neutralization in case of overdose and/or severe bleeding are currently available. In this review, we describe the pharmacology of the DOAC, the efficacy, and safety data from pivotal studies that support their currently approved indications and discuss the postmarketing experience available. We also summarize practical recommendations to ensure an appropriate use of the DOAC according to existing data. Finally, we discuss relevant ongoing studies and future perspectives.

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.

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.

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.

Pharmacoeconomic evaluation of dabigatran, rivaroxaban and apixaban versus enoxaparin for the prevention of venous thromboembolism after total hip or knee replacement in Spain.

BACKGROUND: Patients undergoing total hip replacement (THR) or total knee replacement (TKR) surgery are at high risk of developing venous thromboembolism (VTE). Thromboprophylaxis with low-molecular-weight heparin, such as enoxaparin, is standard of care in these patients. Recently, three direct oral anticoagulants (DOACs; dabigatran, rivaroxaban and apixaban), have been approved for this indication, but their cost effectiveness is still unclear as it has usually been extrapolated from surrogate venographic outcomes in clinical trials. OBJECTIVE: To conduct a pharmacoeconomic evaluation of the DOACs versus subcutaneous (SC) enoxaparin for the prevention of VTE after THR or TKR surgery. METHODS: A decision-tree model was developed using TreeAge Pro 2011 to compare the cost utility and cost effectiveness of the DOACs with SC enoxaparin, with separate models for THR and TKR over a 3-month postoperative time horizon from the perspective of the Spanish National Health System. The probabilities of events (symptomatic VTE, clinically relevant bleedings, heparin-induced thrombocytopenia and deaths) were derived from a systematic review and meta-analysis. We used local cost estimates (€2013) and utility values were obtained from the literature. We reported costs, quality-adjusted life-years (QALYs) and symptomatic VTE events. We conducted sensitivity analyses to evaluate parameter uncertainty. RESULTS: The average costs per 1,000 patients treated with enoxaparin were higher than costs incurred by dabigatran, rivaroxaban and apixaban in THR (€435,208 vs. €283,574, €257,900 and €212,472, respectively) and TKR (€336,550 vs. €219,856, €251,734 and €201,946, respectively), with cost savings ranging from €151,634 to €222,766 in THR, and from €84,816 to €134,604 in TKR. Cost differences were largely driven by differences in costs associated with drug administration. The average QALYs per 1,000 patients treated were very similar for enoxaparin, dabigatran, rivaroxaban and apixaban in THR (199.34, 198.83, 199.08 and 199.68, respectively) and TKR (198.95, 199.41, 198.75 and 199.97, respectively). Rivaroxaban (in TKR and THR) and apixaban (in THR) avoided additional symptomatic VTE events compared with enoxaparin. Sensitivity analyses generally supported the robustness of the analysis to changes in model parameters. CONCLUSIONS: Our model suggests, based on its underlying assumptions and data, that the DOACs are cost-saving alternatives to SC enoxaparin for the prevention of VTE after THR or TKR, in the Spanish healthcare setting.

Longissimus dorsi transcriptome analysis of purebred and crossbred Iberian pigs differing in muscle characteristics.

BACKGROUND: The two main genetic types in Iberian pig production show important phenotypic differences in growth, fattening and tissue composition since early developmental stages. The objective of this work was the evaluation of muscle transcriptome profile in piglets of both genetic types, in order to identify genes, pathways and regulatory factors responsible for their phenotypic differences. Contemporary families coming from pure Iberian pigs (IB) or from crossing with Duroc boars (DU×IB) were generated. Piglets (14 from each genetic type) were slaughtered at weaning (28 days) and longissimus dorsi was sampled for composition and gene expression studies. RNA was obtained and hybridized to Affymetrix Porcine Genechip expression arrays. RESULTS: Loin muscle chemical composition showed significant differences between genetic types in intramuscular fat content (6.1% vs. 4.3% in IB and DUxIB animals, respectively, P = 0.009) and in saturated (P = 0.019) and monounsaturated fatty acid proportions (P = 0.044). The statistical analysis of gene expression data allowed the identification of 256 differentially expressed (DE) genes between genetic types (FDR < 0.10), 102 upregulated in IB and 154 upregulated in DU×IB. Transcript differences were validated for a subset of DE genes by qPCR. We observed alteration in biological functions related to extracellular matrix function and organization, cellular adhesion, muscle growth, lipid metabolism and proteolysis. Candidate genes with known effects on muscle growth were found among the DE genes upregulated in DU×IB. Genes related to lipid metabolism and proteolysis were found among those upregulated in IB. Regulatory factors (RF) potentially involved in the expression differences were identified by calculating the regulatory impact factors. Twenty-nine RF were found, some of them with known relationship with tissue development (MSTN, SIX4, IRX3), adipogenesis (CEBPD, PPARGC1B), or extracellular matrix processes (MAX, MXI1). Correlation among the expression of these RF and DE genes show relevant differences between genetic types. CONCLUSION: These results provide valuable information about genetic mechanisms determining the phenotypic differences on growth and meat quality between the genetic types studied, mainly related to the development and function of the extracellular matrix and also to some metabolic processes as proteolysis and lipid metabolism. Transcription factors and regulatory mechanisms are proposed for these altered biological functions.