ß-alanine supplementation improves in-vivo fresh and fatigued skeletal muscle relaxation speed.

PURPOSE: In fresh muscle, supplementation with the rate-limiting precursor of carnosine, ß-alanine (BA), results in a decline in muscle half-relaxation time (HRT) potentially via alterations to calcium (Ca2+) handling. Accumulation of hydrogen cation (H+) has been shown to impact Ca2+ signalling during muscular contraction, carnosine has the potential to serve as a cytoplasmic regulator of Ca2+ and H+ coupling, since it binds to both ions. The present study examined the effect of BA supplementation on intrinsic in-vivo isometric knee extensor force production and muscle contractility in both fresh and fatigued human skeletal muscle assessed during voluntary and electrically evoked (nerve and superficial muscle stimulation) contractions. METHODS: Twenty-three males completed two experimental sessions, pre- and post- 28 day supplementation with 6.4 g.day-1 of BA (n = 12) or placebo (PLA; n = 11). Isometric force was recorded during a series of voluntary and electrically evoked knee extensor contractions. RESULTS: BA supplementation had no effect on voluntary or electrically evoked isometric force production, or twitch electromechanical delay and time-to-peak tension. There was a significant decline in muscle HRT in fresh and fatigued muscle conditions during both resting (3 ± 13%; 19 ± 26%) and potentiated (1 ± 15%; 2 ± 20%) twitch contractions. CONCLUSIONS: The mechanism for reduced HRT in fresh and fatigued skeletal muscle following BA supplementation is unclear. Due to the importance of muscle relaxation on total energy consumption, especially during short, repeated contractions, BA supplementation may prove to be beneficial in minimising contractile slowing induced by fatigue. TRIAL REGISTRATION: The trial is registered with Clinicaltrials.gov, ID number NCT02819505.

Performance effects of acute ß-alanine induced paresthesia in competitive cyclists.

ß-alanine is a common ingredient in supplements consumed by athletes. Indeed, athletes may believe that the ß-alanine induced paresthesia, experienced shortly after ingestion, is associated with its ergogenic effect despite no scientific mechanism supporting this notion. The present study examined changes in cycling performance under conditions of ß-alanine induced paresthesia. Eight competitive cyclists (VO2max = 61.8 ± 4.2 mL·kg·min(-1)) performed three practices, one baseline and four experimental trials. The experimental trials comprised a 1-km cycling time trial under four conditions with varying information (i.e., athlete informed ß-alanine or placebo) and supplement content (athlete received ß-alanine or placebo) delivered to the cyclist: informed ß-alanine/received ß-alanine, informed placebo/received ß-alanine, informed ß-alanine/received placebo and informed placebo/received placebo. Questionnaires were undertaken exploring the cyclists' experience of the effects of the experimental conditions. A possibly likely increase in mean power was associated with conditions in which ß-alanine was administered (±95% CL: 2.2% ± 4.0%), but these results were inconclusive for performance enhancement (p = 0.32, effect size = 0.18, smallest worthwhile change = 56% beneficial). A possibly harmful effect was observed when cyclists were correctly informed that they had ingested a placebo (-1.0% ± 1.9%). Questionnaire data suggested that ß-alanine ingestion resulted in evident sensory side effects and six cyclists reported placebo effects. Acute ingestion of ß-alanine is not associated with improved 1-km TT performance in competitive cyclists. These findings are in contrast to the athlete's "belief" as cyclists reported improved energy and the ability to sustain a higher power output under conditions of ß-alanine induced paresthesia.

Nutritional Strategies to Modulate Intracellular and Extracellular Buffering Capacity During High-Intensity Exercise.

Intramuscular acidosis is a contributing factor to fatigue during high-intensity exercise. Many nutritional strategies aiming to increase intra- and extracellular buffering capacity have been investigated. Among these, supplementation of beta-alanine (~3-6.4 g/day for 4 weeks or longer), the rate-limiting factor to the intramuscular synthesis of carnosine (i.e. an intracellular buffer), has been shown to result in positive effects on exercise performance in which acidosis is a contributing factor to fatigue. Furthermore, sodium bicarbonate, sodium citrate and sodium/calcium lactate supplementation have been employed in an attempt to increase the extracellular buffering capacity. Although all attempts have increased blood bicarbonate concentrations, evidence indicates that sodium bicarbonate (0.3 g/kg body mass) is the most effective in improving high-intensity exercise performance. The evidence supporting the ergogenic effects of sodium citrate and lactate remain weak. These nutritional strategies are not without side effects, as gastrointestinal distress is often associated with the effective doses of sodium bicarbonate, sodium citrate and calcium lactate. Similarly, paresthesia (i.e. tingling sensation of the skin) is currently the only known side effect associated with beta-alanine supplementation, and it is caused by the acute elevation in plasma beta-alanine concentration after a single dose of beta-alanine. Finally, the co-supplementation of beta-alanine and sodium bicarbonate may result in additive ergogenic gains during high-intensity exercise, although studies are required to investigate this combination in a wide range of sports.

Glucagon receptor antagonism induces increased cholesterol absorption.

Glucagon and insulin have opposing action in governing glucose homeostasis. In type 2 diabetes mellitus (T2DM), plasma glucagon is characteristically elevated, contributing to increased gluconeogenesis and hyperglycemia. Therefore, glucagon receptor (GCGR) antagonism has been proposed as a pharmacologic approach to treat T2DM. In support of this concept, a potent small-molecule GCGR antagonist (GRA), MK-0893, demonstrated dose-dependent efficacy to reduce hyperglycemia, with an HbA1c reduction of 1.5% at the 80 mg dose for 12 weeks in T2DM. However, GRA treatment was associated with dose-dependent elevation of plasma LDL-cholesterol (LDL-c). The current studies investigated the cause for increased LDL-c. We report findings that link MK-0893 with increased glucagon-like peptide 2 and cholesterol absorption. There was not, however, a GRA-related modulation of cholesterol synthesis. These findings were replicated using structurally diverse GRAs. To examine potential pharmacologic mitigation, coadministration of ezetimibe (a potent inhibitor of cholesterol absorption) in mice abrogated the GRA-associated increase of LDL-c. Although the molecular mechanism is unknown, our results provide a novel finding by which glucagon and, hence, GCGR antagonism govern cholesterol metabolism.

[Prophylaxis of thromboembolism in atrial fibrillation: new oral anticoagulants and left atrial appendage closure]. / Embolieprophylaxe bei Vorhofflimmern: Neue orale Antikoagulanzien und Vorhofohrverschluss.

Thrombo-embolic prophylaxis is a key element within the therapy of atrial fibrillation/atrial flutter. Besides new oral anticoagulants the concept of left atrial appendage occlusion has approved to be a good alternative option, especially in patients with increased risk of bleeding.

Novel oral anticoagulants: efficacy, laboratory measurement, and approaches to emergent reversal.

Warfarin, the most commonly used of the vitamin K antagonists, has been a mainstay of oral anticoagulation for decades. However, its usage is limited by morbidity and mortality secondary to bleeding as well as a cumbersome therapeutic monitoring process. In the past several years, a number of competing novel oral anticoagulants (NOACs) have been developed, each of which aspires to match or exceed warfarin's effectiveness while mitigating bleeding risk and eliminating therapeutic monitoring requirements. At present, 1 oral direct thrombin inhibitor and 2 direct factor Xa inhibitors are approved by the US Food and Drug Administration. Here, we compare the clinical efficacy and safety profiles of these new drugs. In addition, we discuss various laboratory assays that may be useful to measure these drugs in certain clinical circumstances. Finally, we discuss emerging strategies to reverse these agents in an emergency. The purpose of this article is to provide a framework for practicing pathologists to advise clinicians on NOAC laboratory measurement and management of NOAC-associated bleeding.

[Retrospective study about 73 consecutive patients treated by direct oral anticoagulant and admitted to an emergency room]. / Étude rétrospective concernant 73 patients traités par un anticoagulant oral direct admis consécutivement dans un service d'urgence.

INTRODUCTION: Direct oral anticoagulants are a recent alternative to vitamin K antagonists but there is a lack of data regarding patients receiving these new types of treatment. The aim of the study was to identify and describe patients receiving direct oral anticoagulants admitted to an emergency unit. METHODS: All the patients taking direct oral anticoagulants, admitted to the emergency room of the Clermont-Ferrand Hospital from January to August 2013, were included in this retrospective and descriptive study. RESULTS: Among the 73 patients included, 47.9% were treated with dabigatran and 52.1% with rivaroxaban. The indication was stroke prevention in 62 patients with atrial fibrillation whose average CHADS2 score was 2.6 [2.3-3](IC95%). The average age was 76.4 years [73.7-79.1](IC95%). Twenty-nine patients (39.7%) had at least one drug association known for increasing the risk of bleeding. Average scores for bleeding risk were: HAS-BLED 3.1 [2.9-3.3](IC95%) and Beyth 1.5 [1.3-1.6](IC95%). Bleeding patients included a higher percentage of men (68.8 vs. 38.2%, P=0.032). Creatinine clearance was lower in patients with major bleeding (45.2% vs. 68.8 mL/min, P=0.002). The Beyth score was highest in both sub-groups. CONCLUSION: In our study, we have found that the bleeding risk factors were: male gender, a high Beyth score, and a lowered creatinine clearance. Overall, patients treated with direct oral anticoagulants admitted to the emergency room were old with many co-morbidities, especially cardiovascular conditions; polymedication was frequent.

Dabigatran and rivaroxaban use in atrial fibrillation patients on hemodialysis.

BACKGROUND: Dabigatran and rivaroxaban are new oral anticoagulants that are eliminated through the kidneys. Their use in dialysis patients is discouraged because these drugs can bioaccumulate to precipitate inadvertent bleeding. We wanted to determine whether prescription of dabigatran or rivaroxaban was occurring in the dialysis population and whether these practices were safe. METHODS AND RESULTS: Prevalence plots were used to describe the point prevalence (monthly) of dabigatran and rivaroxaban use among 29977 hemodialysis patients with atrial fibrillation. Poisson regression compared the rate of bleeding, stroke, and arterial embolism in patients who started dabigatran, rivaroxaban, or warfarin. The first record of dabigatran prescription among hemodialysis patients occurred 45 days after the drug became available in the United States. Since then, dabigatran and rivaroxaban use in the atrial fibrillation-end-stage renal disease population has steadily risen where 5.9% of anticoagulated dialysis patients are started on dabigatrian or rivaroxaban. In covariate adjusted Poisson regression, dabigatran (rate ratio, 1.48; 95% confidence interval, 1.21-1.81; P=0.0001) and rivaroxaban (rate ratio, 1.38; 95% confidence interval, 1.03-1.83; P=0.04) associated with a higher risk of hospitalization or death from bleeding when compared with warfarin. The risk of hemorrhagic death was even larger with dabigatran (rate ratio, 1.78; 95% confidence interval, 1.18-2.68; P=0.006) and rivaroxaban (rate ratio, 1.71; 95% confidence interval, 0.94-3.12; P=0.07) relative to warfarin. There were too few events in the study to detect meaningful differences in stroke and arterial embolism between the drug groups. CONCLUSIONS: More dialysis patients are being started on dabigatran and rivaroxaban, even when their use is contraindicated and there are no studies to support that the benefits outweigh the risks of these drugs in end-stage renal disease.

Efectos de la suplementación con ß-alanina sobre el rendimiento deportivo / Effects of B-alanine supplementation on Athletic performance

La carnosina, dipéptido formado por los aminoácidos ß-alanina y L-histidina, tiene importantes funciones fisiológicas entre las que destaca su función antioxidante y las relacionadas con la memoria y el aprendizaje. Sin embargo, en relación con el ejercicio, las funciones más importantes serían las relacionadas con la contractilidad muscular, al mejorar la sensibilidad al calcio en las fibras musculares, y la función reguladora del pH. De este modo, se ha propuesto que la carnosina es el principal tampón intracelular, pudiendo llegar a contribuir hasta un 7-10% en la capacidad buffer o tampón. Dado que la síntesis de carnosina parece estar limitada por la disponibilidad de ß-alanina, la suplementación con este compuesto ha ido ganando cada vez más popularidad entre la población deportista. Por ello, el objetivo del presente estudio de revisión bibliográfica ha sido el de estudiar todos aquellos trabajos de investigación que han comprobado el efecto de la suplementación con ß-alanina sobre el rendimiento deportivo. Por otra parte, también, se ha intentado establecer una posología específica que, maximizando los posibles efectos beneficiosos, reduzca al mínimo la parestesia, el principal efecto secundario presentado como respuesta a la suplementación (AU)

Carnosine, dipeptide formed by amino acids ß-alanine and L-histidine, has important physiological functions among which its antioxidant and related memory and learning. However, in connection with the exercise, the most important functions would be associated with muscle contractility, improving calcium sensitivity in muscle fibers, and the regulatory function of pH. Thus, it is proposed that carnosine is the major intracellular buffer, but could contribute to 7-10% in buffer or buffer capacity. Since carnosine synthesis seems to be limited by the availability of ß-alanine supplementation with this compound has been gaining increasing popularity among the athlete population. Therefore, the objective of this study literature review was to examine all those research works have shown the effect of ß-alanine supplementation on athletic performance. Moreover, it also has attempted to establish a specific dosage that maximizing the potential benefits, minimize paresthesia, the main side effect presented in response to supplementation (AU)

[Comparison of the safety of rivaroxaban versus dabigatran therapy in patients with persistent atrial fibrillation]. / Porównanie bezpieczenstwa terapii rywaroksabanem i dabigatranem u pacjentów chorych na przetrwale migotanie przedsionków.

UNLABELLED: For 60 years, vitamin K antagonists have been used in prevention of thromboembolic complications in the course of atrial fibrillation (AF), however such therapy is associated with many inconveniences. New oral anticoagulants (NOAC), rivaroxaban and dabigatran, represent an attractive alternative to VKA. THE AIM OF THE STUDY: Yo evaluate the safety of a 6-month therapy with rivaroxaban and dabigatran in patients (pts) with persistent AF. MATERIALS AND METHODS: The analysis included 24 pts (14 females, 10 males) with nonvalvular AF and indications for oral anticoagulant therapy (CHA2DS2-VASc > or = 2, HAS-BLED < 3), hospitalized in the Clinic of Internal Diseases and Clinical Pharmacology of the Medical University of Lodz between July 2012 and September 2013. In the group of patients treated chronically with VKA, laboratory tests (GFR, creatinine, ALT AST, coagulation) were performed during their stay in the clinic. The patients were randomly assigned to the treatment with one of the new NOACs, rivaroxaban or dabigatran. After a 6-month period, the patients completed a questionnaire on their general health condition and follow-up laboratory tests were performed. RESULTS: In the group of pts. receiving dabigatran INR increased by 23% (p = 0.0002) and APTT prolongation by 91% was noted (p = 0.0004) whereas in the group of pts receiving rivaroxaban an INR increase by 17% (p = 0.04) and APTT prolongation by 32% (p = 0.0043) were observed. After a 6-month therapy, dabigatran prolongs APTT significantly more, as compared to rivaroxaban (p=0.0002). Among patients using dabigatran, 16.7% experienced the following symptoms: abdominal pain, gastritis, nausea. 8.3% patients experienced bleeding from haemorrhoids, easier bruising. In the group of patients receiving rivaroxaban, 16.7% experienced the following symptoms: nosebleeds and easier bruising; 8.3%: bleeding from gums, haematuria. 25%: pruritus, rash: 8.3%. The hazard ratio (HR) for occurrence of dyspeptic symptoms was 1.13 for dabigatran. Minor bleeding is 3.6 times more common when using rivaroxaban. CONCLUSIONS: Significant increase of INR and prolongation of APTT are observed after a 6-month therapy with rivaroxaban or dabigatran. Additionally, dabigatran significantly prolongs the prothrombin time. Despite the fact that dabigatran caused larger prolongation of APTT minor bleeding episodes occurred more frequently in patients treated with rivaroxaban. No worsening of kidney or liver function was observed during the 6-month therapy with rivaroxaban or dabigatran. Rywaroxaban more frequently causes minor bleeding, whereas treatment with dabigatran is associated with more frequent gastrointestinal adverse symptoms.

Novel oral anticoagulants in non-valvular atrial fibrillation.

Atrial fibrillation is the most frequent arrhythmia in clinical practice, reaching 2% of the people in the world and is associated with systemic embolism. Thus, the use of anticoagulants is indicated if CHA2DS2-VASc score ≥ 2 or in patients with previous transient ischemic attack or stroke. For decades, warfarin, a vitamin K antagonist, was the only choice for chronic oral anticoagulation. Recently, novel oral anticoagulants (NOACs) have been introduced, offering similar (or better) effectiveness, safety, and convenience to the vitamin K antagonists. Dabigatran was the first NOAC approved and is a direct thrombin inhibitor. Rivaroxaban and apixaban are factor Xa inhibitors. They display rapid onset of action, more predictable of pharmacological profile, less interactions with other drugs, lack of significant effects in the diet, and less risk of intracranial hemorrhage than warfarin. Despite that dose adjustment is necessary for patients with chronic kidney disease or according to body weight, these new drugs do not require regular monitoring. There are recommendations for the start and follow-up therapy with NOACs, planning for cardioversion, ablation and surgical interventions and the management of bleeding. This article is a review of the major studies of the NOACs. The clinical use of these drugs in patients with non-valvular atrial fibrillation is presented.

Strategies for urgent reversal of target-specific oral anticoagulants.

The direct thrombin inhibitor dabigatran and factor Xa inhibitors rivaroxaban and apixaban are US Food and Drug Administration (FDA)-approved target-specific oral anticoagulants (TSOACs) that have emerged onto the market for use in some indications similar to those for warfarin; in addition, edoxaban is seeking FDA approval. Similar indications include reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation for all 3 agents, for the prevention of deep vein thrombosis that may lead to pulmonary embolism in patients undergoing hip or knee surgery for rivaroxaban and apixaban, and for the treatment and prevention of deep vein thrombosis and pulmonary embolism. As anticoagulants, they are all associated with a risk of bleeding, and, unfortunately, there are no approved antidotes for reversal of these agents. A number of small studies in human subjects and in human/animal models exposed to TSOACs have evaluated the use of activated charcoal, hemodialysis for dabigatran, or clotting factor concentrates for their ability to neutralize the anticoagulant effects or reduce drug concentrations of TSOACs. Clotting factor concentrates that have been used include prothrombin complex concentrates and recombinant factor VII. This review examines studies and case reports evaluating these strategies for expedited or emergent reversal of TSOACs.

A comparison of bleeding complications between warfarin, dabigatran, and rivaroxaban in patients undergoing cryoballoon ablation.

INTRODUCTION: In recent years, several novel anticoagulants have been approved for the prevention of thromboembolic strokes as an alternative to warfarin in patients with atrial arrhythmias. Studies have evaluated these medications in patients undergoing radiofrequency ablation, yet no data exists to evaluate the bleeding risk in patients undergoing cryoballoon ablation procedures. METHODS: Patients that underwent either cryoballoon ablation alone or with additional radiofrequency ablation over the past 3 years were included in the study. Patients were stratified into one of three subsets based on type of anticoagulation (warfarin, dabigatran, or rivaroxaban). Bleeding complications during the first 48 h and first 2 weeks following the ablation were recorded. Major complications were defined as hemorrhage requiring blood products or need for vascular intervention. Minor complications included prolonged bleeding from catheter insertion site, development of ecchymosis, or hematoma formation. Intraprocedural activated clotting times (ACT) were assessed and compared. RESULTS: A total of 217 patients met inclusion criteria of which 87 (40.1 %) patients were on warfarin, 90 (41.5 %) patients on dabigatran, and 40 (18.4 %) patients on rivaroxaban. The overall bleeding complication rate was 12.0 %. All complications occurred within the first 48 h post-ablation. Nine (10.3 %) complications occurred in the warfarin subset, ten (11.1 %) in the rivaroxaban subset, and seven (17.5 %) in the dabigatran subset (p = 0.49). The warfarin and dabigatran subsets had higher average ACT levels (424.9 versus 406.5) compared to the rivaroxaban subset (393.4; p < 0.01). Subanalyses found no difference in bleeding complications based on procedure type. CONCLUSION: Bleeding complications post-ablation were similar for warfarin, dabigatran, and rivaroxaban in patients undergoing cryoballoon ablation. Compared with radiofrequency ablation, cryoablation does not place patients at an increased bleeding risk.

Approach to the new oral anticoagulants in family practice: part 1: comparing the options.

OBJECTIVE: To compare key features of the new oral anticoagulants (NOACs)-dabigatran, rivaroxaban, and apixaban-and to address questions that arise when comparing the NOACs. SOURCES OF INFORMATION: PubMed was searched for recent (January 2008 to week 32 of 2013) clinical studies relating to NOAC use for stroke prevention in atrial fibrillation (AF) and for the treatment of acute venous thromboembolism (VTE). MAIN MESSAGE: All NOACs are at least as effective as warfarin for stroke prevention in patients with nonvalvular AF, and are at least as safe in terms of bleeding risk according to 3 large trials. Meta-analyses of these trials have shown that, compared with warfarin therapy, NOACs reduced total mortality, cardiovascular mortality, and intracranial bleeding, and there was a trend toward less overall bleeding. Practical advantages of NOACs over warfarin include fixed once- or twice-daily oral dosing without the need for coagulation monitoring, and few known or defined drug or food interactions. Potential drawbacks of NOACs include a risk of bleeding that might be increased in patients older than 75 years, increased major gastrointestinal bleeding with high-dose dabigatran, increased dyspepsia with dabigatran, the lack of a routine laboratory test to reliably measure anticoagulant effect, and the lack of an antidote for reversal. No direct comparisons of NOACs have been made in randomized controlled trials, and the choice of NOAC is influenced by individual patient characteristics, including risk of stroke or VTE, risk of bleeding, and comorbidity (eg, renal dysfunction). CONCLUSION: The NOACs represent important alternatives in the management of patients with AF and VTE, especially for patients who have difficulty accessing regular coagulation monitoring. The companion to this article addresses common "what if" questions that arise in the long-term clinical follow-up and management of patients receiving NOACs.

Antithrombotic triple therapy and coagulation activation at the site of thrombus formation: a randomized trial in healthy subjects.

BACKGROUND: Patients with acute coronary syndrome and concomitant atrial fibrillation may require antithrombotic triple therapy but clinical evidence of safety and efficacy is poor. We have therefore studied the combination of different antithrombotic medicines for coagulation activation in an in vivo model in the skin microvasculature. METHODS AND RESULTS: Platelet activation (ß-thromboglobulin [ß-TG]) and thrombin generation (prothrombin fragment 1 + 2 [F1+2 ], thrombin-antithrombin complex [TAT]) were studied in an open-label, randomized, parallel group trial in 60 healthy male subjects (n = 20 per group) who received ticagrelor and acetylsalicylic acid (ASA) in combination with dabigatran (150 mg bid), rivaroxaban (20 mg od) or phenprocoumon (INR 2.0-3.0). Coagulation biomarkers in shed blood were assessed at 3 h after monotherapy with the medicines under study, at 3 h after triple therapy dosing and at steady state trough conditions. Single doses of ticagrelor, dabigatran or rivaroxaban caused comparable decreases in shed blood ß-TG and were more pronounced than phenprocoumon at an INR of 2.0-3.0. In contrast, thrombin generation was more affected by rivaroxaban and phenprocoumon than by dabigatran. During triple therapy a similarly sustained inhibition of platelet activation and thrombin generation with a maximum decrease of ß-TG, F1+2 and TAT at 3 h post-dosing was noted, which remained below pre-dose levels at trough steady state. CONCLUSION: A triple therapy at steady state with ticagrelor plus ASA in combination with dabigatran or rivaroxaban is as effective as a combination with phenprocoumon for platelet activation and thrombin generation in vivo.

[Eligibility for dabigatran therapy: the real-life experience of a Tuscany general hospital]. / Eleggibilità al trattamento con dabigatran: esperienza real-life di un policlinico toscano.

Introduction. Dabigatran has emerged as a promising alternative to vitamin K antagonists (VKAs) in non-valvular atrial fibrillation (NVAF). It has several clinical and practical advantages over VKAs that finally facilitate their use in clinical practice. The aim of this study is to describe patients taking dabigatran, to evaluate its use in the real world and the eligibility for therapy, according to the criteria established by the Italian Medicines Agency (AIFA). Methods. A retrospective review was conducted using dabigatran prescriptions in patients with NVAF. Data were retrieved from the prescriptions recorded in the hospital pharmacy of Careggi General Hospital from June to October 2013. Results. Data were related to 138 patients with NVAF who have at least one dabigatran prescription. Patients have a mean age of 79.0 ± 8.9 years, mean CHA2DS2-VASc 4.4 ± 3.0 and mean HAS-BLED 3.0 ± 1.0. 49.3% were male and 50% were older than 80 years; 18.8% were treated with high-dose dabigatran (150 mg). According to the AIFA criteria, 85.5% of patients were eligible for treatment: 34% were at high embolic and bleeding risk and 70.2% reported objective problems in routine coagulation monitoring. Conclusions. Our patients can be categorized in two groups: subjects with high risk of embolism and bleeding for whom the new oral anticoagulant dabigatran provides clinically important benefit, and subjects for whom the benefit derives from a simplified management of therapy. It should be interesting to evaluate the rate of therapeutic adherence in these patients in order to verify the expected clinical benefits.

Dabigatran, rivaroxaban and apixaban for extended venous thromboembolism treatment: network meta-analysis.

AIM: Many new oral anticoagulants (NOACs; dabigatran, rivaroxaban, and apixaban) are currently available to treat thromboembolic disease. There are no head-to-head trials comparing these agents. To assess the efficacy and safety of NOACs for prevention of recurrent venous thromboembolism (VTE), we performed a network meta-analysis. METHODS: Medline, Embase, and the Cochrane-controlled trial register were searched, without language restriction, to identify trials. Studies were evaluated according to a priori inclusion criteria and appraised using established internal validity criteria. Adjusted indirect comparisons between agents were performed using well-established methods. RESULTS: Three trials meeting inclusion criteria were identified. Direct comparison between apixaban 2.5 mg twice daily (BID) versus apixaban 5 mg BID showed no difference for any outcome. Clinically relevant non-major bleeding occurred less with both apixaban 2.5 mg BID (OR 0.23, 95% CI 0.08-0.62, P=0.004) and apixaban 5 mg BID [OR 0.31, 95% CI 0.11-0.82, P=0.019] compared to rivaroxaban 20 mg daily. Apixaban 2.5 mg BID showed less clinically relevant non-major bleeding than dabigatran 150 mg BID [OR 0.4, 95% CI 0.16-0.9, P=0.04], but not apixaban 5 mg BID. There were no differences between rivaroxaban 20 mg daily and dabigatran 150 mg BID. No differences in risk for recurrent VTE, major bleeding, or mortality were observed for any comparison between any pair of NOACs. CONCLUSION: There were no significant differences in risk for recurrent VTE, major bleeding, or all-cause mortality between the NOACs. However, apixaban 2.5 mg BID was associated with less clinically significant non-major bleeding than either rivaroxaban 20 mg daily or dabigatran 150 mg BID.