Treatment of acute pulmonary embolism after catheter-directed thrombolysis with dabigatran vs warfarin: Results of a multicenter randomized RE-SPIRE trial.

BACKGROUND: Thrombolytic therapy is effective method in the high-risk acute pulmonary embolism (PE) treatment. Reduced-dose thrombolysis (RDT) plus oral anticoagulation therapy is effective and safe method in the moderate and severe PE treatment. It is leading to good early and intermediate-term outcomes. In the RE-COVER and RE-COVER II studies, dabigatran showed similar effectiveness as warfarin in the treatment of acute PE. Dabigatran leads to fewer hemorrhagic complications and is not inferior in efficacy to warfarin in the prevention of PE after mechanical fragmentation and RDT (catheter-directed treatment [CDT]+RDT) in patients with high and intermediate to high PE risk. We sought to evaluate the efficacy and safety (incidence of clinically significant recurrence of venous thromboembolic complications and deaths) during a 6-month course of treatment with dabigatran or warfarin in patients with high and intermediate to high acute PE risk after endovascular mechanical thrombus fragmentation procedure with RDT (CDT+RDT). METHODS: The RE-SPIRE is a prospective, multicenter randomized double-arm study. Over a 5-year period, 66 consecutive patients with symptomatic high and intermediate to high PE risk after endovascular mechanical thrombus fragmentation procedure with RDT (CDT+RDT) were randomized into two groups within the next 48 hours. The first group continued treatment with dabigatran 150 mg twice a day for 6 months; the second group continued treatment with warfarin under the control of international normalized ratio (2.0-3.0) for 6 months. Both groups received low molecular weight heparins for 2 days after surgery. Then, group 1 continued to receive low molecular-weight-heparin for 5 to 7 days, followed by a switch to dabigatran at a dosage of 150 mg two times a day. Group 2 received both low-molecular-weight heparin and warfarin up to an international normalized ratio of >2.0, followed by heparin withdrawal. The follow-up period was 6 months. RESULTS: There were 63 patients who completed the study (32 in the dabigatran group and 31 in the warfarin group). In both groups, there was a statistically significant decrease in the mean pulmonary artery pressure. The mean pulmonary artery pressure at the 6-month follow-up after surgery was 24 mm Hg (interquartile range, 20.3-29.25 mm Hg) in the dabigatran group and 23 mm Hg (interquartile range, 20.0-26.3 mm Hg) in the warfarin group. The groups did not differ statistically in the deep vein thrombosis dynamics. Partial recanalization occurred in 52.0% vs 73.1% in the dabigatran and warfarin groups, respectively (P = .15). Complete recanalization occurred in 28.0% vs 19.2% in the dabigatran and warfarin groups, respectively (P = .56). The groups did not differ in the frequency of major bleeding events according to the International Society for Thrombosis and Hemostasis (0% vs 3.2% in the dabigatran and warfarin groups, respectively; P = 1.00). However, there were more nonmajor bleeding events in the warfarin group than in the dabigatran group (16.1% vs 0%, respectively; P = .02). CONCLUSIONS: The results of the study show that dabigatran is comparable in effectiveness to warfarin. Dabigatran has greater safety in comparison with warfarin in the occurrence of all cases of bleeding in the postoperative and long-term periods. Thus, dabigatran may be recommended for the treatment and prevention of PE after CDT with RDT in patients with high and intermediate to high PE risk.

The effect of multi-ingredient intra- versus extra-cellular buffering supplementation combined with branched-chain amino acids and creatine on exercise-induced ammonia blood concentration and aerobic capacity in taekwondo athletes.

BACKGROUND: This study aimed to investigate the effect of multi-ingredient intra- (BA) versus extra- (ALK) cellular buffering factor supplementation, combined with the customary intake of branched-chain amino acids (BCAA) and creatine malate (TCM), on body composition, exercise variables, and biochemical and hematological parameters in 9 elite taekwondo athletes. METHODS: Eight-week randomized double-blind crossover BA (5.0 g·day-1 of ß-alanine) versus ALK (0.07 g·kgFFM-1·day-1 of sodium bicarbonate) supplementation combined with BCAA (0.2 g·kgFFM-1·day-1) and TCM (0.05 g·kgFFM-1·day-1) during a standard 8-week taekwondo training period was implemented. In the course of the experiment, body composition (dual X-ray absorptiometry), aerobic capacity (ergospirometric measurements during an incremental treadmill test until exhaustion), and exercise blood biomarkers concentrations were measured. Data were analyzed using repeated measures within-between interaction analysis of variance with the inclusion of experimental supplementation order. RESULTS: The maximum post-exercise blood ammonia concentration decreased in both groups after supplementation (from 80.3 ± 10.6 to 72.4 ± 10.2 µmol∙L-1, p = 0.013 in BA; from 81.4 ± 8.7 to 74.2 ± 8.9 µmol∙L-1, p = 0.027 in ALK), indicating reduced exercise-related adenosine triphosphate degradation. However, no differences were found in body composition, aerobic capacity, blood lactate concentration, and hematological parameters after neither BA (combined with BCAA and TCM) nor ALK (combined with BCAA and TCM) supplementation. CONCLUSIONS: In highly trained taekwondo athletes, neither extra- nor intracellular buffering enhancement resulting from BA and ALK supplementation, combined with BCAA and TCM treatment, affects body mass and composition, maximum oxygen uptake, and hematological indices, even though certain advantageous metabolic adaptations can be observed.

Transient Reticular Cystic Corneal Epithelial Edema With Topical Netarsudil: A Case Series and Review.

PURPOSE: To describe cases in which netarsudil ophthalmic solution 0.02% precipitated reversible, reticular cystic epithelial edema. METHODS: A retrospective case review at the Brooklyn Veteran's Association Hospital of patients with corneal stromal edema that were treated with netarsudil and subsequently developed cystic epithelial edema. RESULTS: Four male patients with a mean age of 72 ± 8.0 years developed a reticular, honeycomb-like pattern of epithelial edema located in the interpalpebral and inferior cornea. In 3 of 4 patients, epithelial edema arose within 1 month compared with 2 months in 1 patient. New epithelial cysts did not correlate with worsening central corneal thickness and best spectacle-corrected visual acuity in every patient, which was likely due to the location of the cysts. Two of 4 patients developed increased central corneal thickness with worsening best spectacle-corrected visual acuity. In comparison, 1 patient had improvement in both parameters, whereas 1 patient had no significant change. In all cases, there was resolution of the epithelial cysts after discontinuation of netarsudil. CONCLUSIONS: Although rho-kinase inhibitors have been suggested to improve endothelial function, we have documented worsening epithelial cysts in a subset of patients with pre-existing corneal edema. These effects of netarsudil were transient and resolved after discontinuing treatment within 2 weeks in most patients. We hypothesize that the incidence of this adverse finding is more common than previously believed. Nevertheless, large-scale studies are needed to accurately report on the incidence and clinical significance of this novel finding.

Women dealing with hot flushes: the role of ß-alanine.

Hot flushes (HFs) are a very frequent condition in menopausal women, associated with a marked decrease in quality of life, impaired ability to carry on daily activities and sleep disturbances. However, this condition is often only given poor attention in daily practice and in clinical research. Indeed, several treatments for HFs exist. The most effective is considered to be hormone replacement therapy, but this strategy has been associated with a poor risk-benefit ratio given its link with the development of cancer. Other treatments have been tested and are currently used, but they are usually only poorly effective or cannot be recommended in all patients due to potential side effects or interference with other molecules. Therefore, there is a major need for new treatment options for HFs. ß-alanine supplementation is widely used for the enhancement of energetic metabolism and is known to be devoid of any relevant adverse effect. BA has also been widely used for the treatment of HFs. This narrative review will discuss the current pharmacological management of HFs and will present the role of ß-alanine in this setting.

ß-Alanine supplementation reduces anxiety and increases neurotrophin expression in both young and older rats.

The effect of 30 days of ß-alanine supplementation (100 mg/kg) on behavioral response and expression of brain-derived neurotrophic factor (BDNF), neuropeptide Y (NPY), and markers of inflammation was examined in both young (4 months) and older (14 months) rats. We hypothesized that animals fed ß-alanine would experience reduced inflammation and an enhanced neurotrophin and behavioral response. Animals were assigned to either a control group, in which young or older rats were fed regular chow and water, or a ß-alanine group, in which rats were fed regular chow and provided ß-alanine in their water. Behavior measures were conducted following the 30-day supplementation period, which included spatial learning, memory, and an anxiety index. Hippocampal expressions of BDNF, NPY, glial fibrillary acidic protein, nuclear factor-κB p50 and p65 subunits, tumor necrosis factor-α, and cyclooxygenase-2 were also analyzed. Learning ability was reduced (P = .001) and anxiety index was higher (P = .001) in older compared to young rats. Similarly, BDNF and NPY expressions were reduced and all inflammatory markers were elevated (P < .05) in the older animals. ß-Alanine increased BDNF expressions in the cornu ammonis area 1 (P = .003) and 3 (P < .001) subregions of the hippocampus. BDNF expression for younger rats in the ß-alanine group was also significantly greater than younger rats in the control group in cornu ammonis area 3. Learning for young animals fed ß-alanine was significantly better than all other groups. Significant reductions in anxiety were noted in both older and younger rats fed ß-alanine compared to age-matched controls. Results indicated that ß-alanine ingestion in both young and older rats was effective in attenuating anxiety and augmenting BDNF expression in the hippocampus.

Direct comparison of 2­amino[3­11C]isobutyric acid and 2­amino[11C]methyl­isobutyric acid uptake in eight lung cancer xenograft models.

The non­natural amino acid positron emission tomography tracers, 2­amino[3­11C]isobutyric acid ([3­11C]AIB) and 2­amino[11C]methyl­isobutyric acid ([11C]MeAIB), are metabolically stable in vivo and accumulate in tumors. [3­11C]AIB is transported into cells mainly via the amino acid transport system A and partially via systems L and ASC, whereas [11C]MeAIB is transported into cells specifically via system A. How transport via the different systems affects the tumor uptake of these tracers, however, is unclear. In the present study, the tumor uptake of the two tracers was directly compared in eight lung cancer models (A549, H82, H441, H460, H1299, H1650, PC14, and SY), and the correlation of tumor uptake with several factors (amino acid transporter expression, contribution of amino acid transport systems to AIB uptake and tumor proliferation indices) was analyzed. Biodistribution analyses revealed that the tumor uptake of [3­11C]AIB (4.9 to 19.2% injected dose per gram [ID/g]) was higher than that of [11C]MeAIB (3.1 to 15.9% ID/g) in all eight tumors, with a statistically significant difference in three tumors (P<0.01 in H441 and H460 tumors, P<0.05 in H82 tumors). A significant correlation was observed between the tumor uptake of the two tracers (r=0.95, P<0.01). The mRNA expression levels of the amino acid transporters of system A (SLC38A1 and SLC38A2), system L (SLC7A5) and system ASC (SLC1A5) were higher in all eight tumors than in the normal lung, with widely varying expression patterns. Although the contributions of the amino acid transport systems, Ki­67 indices and tumor doubling times greatly differed among the eight models, these factors did not correlate with the tumor uptake of either tracer. The higher tumor uptake of [3­11C]AIB and the correlation of tumor uptake between [3­11C]AIB and [11C]MeAIB warrant further investigation in clinical studies in order to clarify the role of [3­11C]AIB PET in oncology imaging.

ß-Alanine mediated inhibition of PTHR1suppresses the proliferation, invasion and tumorigenesis in metastatic human osteosarcoma U2OS cells.

The present study was aimed to investigate the effect of ß-alanine mediated inhibition of parathyroid hormone 1 receptor (PTHR1), suppresses the proliferation, invasion, and tumorigenesis in metastatic human osteosarcoma U2OS cells. Cell survival rate was reduced 96.54, 91.23, 84.62, 76.42 and 69.72% following incubation of ß-alanine at 50-250 mM respectively. Annexin-V/propidium iodide (PI) staining showed a reduced level of viable cells (71.37%) at 250 mM of ß-alanine. U2OS cell proliferation, adhesion, invasion, and migration were decreased following incubation with ß-alanine. Matrix metalloproteinases-2/9 (MMP-2/9) mRNA expression was reduced, whereas tissue inhibitors of metalloproteinases-1/2 (TIMP-1/2) mRNA expression was increased remarkably. The mRNA and protein of PTHR1 were reduced in the cells following incubation with ß-alanine. Vacuole membrane protein 1 (Vmp1) mRNA and protein were increased in the cells following incubation with ß-alanine. In tunel assay, the number of PTHR1 positive cells was 67, 34 and 17 following incubation with ß-alanine at 150, 200 and 250 mM respectively. Taking all these data together, it is concluded that ß-alanine mediated inhibition of PTHR1 reduced the U2OS cell proliferation, invasion, migration, and tumorigenesis. Furthermore, the results indicated that the ß-alanine induced expression of PTHR1 has a positive relationship with invasion and metastasis of osteosarcoma cells.

Comparison of Two ß-Alanine Dosing Protocols on Muscle Carnosine Elevations.

OBJECTIVE: ß-alanine (BA) is a nonproteogenic amino acid that combines with histidine to form carnosine. The amount taken orally in individual doses, however, is limited due to symptoms of paresthesia that are associated with higher doses. The use of a sustained-release formulation has been reported to reduce the symptoms of paresthesia, suggesting that a greater daily dose may be possible. The purpose of the present study was to determine whether increasing the daily dose of BA can result in a similar increase in muscle carnosine in a reduced time. METHODS: Eighteen men and twelve women were randomized into either a placebo (PLC), 6-g BA (6G), or 12-g BA (12G) groups. PLC and 6G were supplemented for 4 weeks, while 12G was supplemented for 2 weeks. A resting blood draw and muscle biopsy were obtained prior to (PRE) and following (POST) supplementation. Plasma and muscle metabolites were measured by high-performance liquid chromatography. The loss in peak torque (ΔPT) was calculated from maximal isometric contractions before and after 250 isokinetic kicks at 180°·sec-1 PRE and POST. RESULTS: Both 12G (p = 0.026) and 6G (p = 0.004) increased muscle carnosine compared to PLC. Plasma histidine was decreased from PRE to POST in 12G compared to PLC (p = 0.002) and 6G (p = 0.001), but no group x time interaction (p = 0.662) was observed for muscle histidine. No differences were observed for any hematological measure (e.g., complete blood counts) or in symptoms of paresthesia among the groups. Although no interaction was noted in ΔPT, a trend (p = 0.073) was observed. CONCLUSION: Results of this investigation indicate that a BA supplementation protocol of 12 g/d-1, using a sustained-release formulation, can accelerate the increase in carnosine content in skeletal muscle while attenuating paresthesia.

Rationally Developed Organic Salts of Tolfenamic Acid and Its ß-Alanine Derivatives for Dual Purposes as an Anti-Inflammatory Topical Gel and Anticancer Agent.

A new series of primary ammonium monocarboxylate (PAM) salts of a nonsteroidal anti-inflammatory drug (NSAID), namely, tolfenamic acid (TA), and its ß-alanine derivatives were generated. Nearly 67 % of the salts in the series showed gelling abilities with various solvents, including water (biogenic solvent) and methyl salicylate (typically used for topical gel formulations). Gels were characterized by rheology, electron microscopy, and so forth. Structure-property correlations based on single-crystal and powder XRD data of several gelator and nongelator salts revealed intriguing insights. Studies (in vitro) on an aggressive human breast cancer cell line (MDA-MB-231) with the l-tyrosine methyl ester salt of TA (S7) revealed that the hydrogelator salt was more effective at killing cancer cells than the mother drug TA (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay); displayed better anti-inflammatory activity compared with that of TA (prostaglandin E2 assay); could be internalized within the cancer cells, as revealed by fluorescence microscopy; and inhibited effectively migration of the cancer cells. Thus, the easily accessible ambidextrous gelator salt S7 can be used for two purposes: as an anti-inflammatory topical gel and as an anticancer agent.

Twenty-four Weeks of ß-Alanine Supplementation on Carnosine Content, Related Genes, and Exercise.

INTRODUCTION: Skeletal muscle carnosine content can be increased through ß-alanine (BA) supplementation, but the maximum increase achievable with supplementation is unknown. No study has investigated the effects of prolonged supplementation on carnosine-related genes or exercise capacity. PURPOSE: This study aimed to investigate the effects of 24 wk of BA supplementation on muscle carnosine content, gene expression, and high-intensity cycling capacity (CCT110%). METHODS: Twenty-five active males were supplemented with 6.4 g·d of sustained release BA or placebo for a 24 wk period. Every 4 wk participants provided a muscle biopsy and performed the CCT110%. Biopsies were analyzed for muscle carnosine content and gene expression (CARNS, TauT, ABAT, CNDP2, PHT1, PEPT2, and PAT1). RESULTS: Carnosine content was increased from baseline at every time point in BA (all P < 0.0001; week 4 = +11.37 ± 7.03 mmol·kg dm, week 8 = +13.88 ± 7.84 mmol·kg dm, week 12 = +16.95 ± 8.54 mmol·kg dm, week 16 = +17.63 ± 8.42 mmol·kg dm, week 20 = +21.20 ± 7.86 mmol·kg dm, and week 24 = +20.15 ± 7.63 mmol·kg dm) but not placebo (all P > 0.05). Maximal increases were +25.66 ± 7.63 mmol·kg dm (range = +17.13 to +41.32 mmol·kg dm), and absolute maximal content was 48.03 ± 8.97 mmol·kg dm (range = 31.79 to 63.92 mmol·kg dm). There was an effect of supplement (P = 0.002) on TauT; no further differences in gene expression were shown. Exercise capacity was improved in BA (P = 0.05) with possible to almost certain improvements across all weeks. CONCLUSIONS: Twenty-four weeks of BA supplementation increased muscle carnosine content and improved high-intensity cycling capacity. The downregulation of TauT suggests it plays an important role in muscle carnosine accumulation with BA supplementation, whereas the variability in changes in muscle carnosine content between individuals suggests that other determinants other than the availability of BA may also bear a major influence on muscle carnosine content.

Plasma carnosine, but not muscle carnosine, attenuates high-fat diet-induced metabolic stress.

There is growing in vivo evidence that the dipeptide carnosine has protective effects in metabolic diseases. A critical unanswered question is whether its site of action is tissues or plasma. This was investigated using oral carnosine versus ß-alanine supplementation in a high-fat diet rat model. Thirty-six male Sprague-Dawley rats received a control diet (CON), a high-fat diet (HF; 60% of energy from fat), the HF diet with 1.8% carnosine (HFcar), or the HF diet with 1% ß-alanine (HFba), as ß-alanine can increase muscle carnosine without increasing plasma carnosine. Insulin sensitivity, inflammatory signaling, and lipoxidative stress were determined in skeletal muscle and blood. In a pilot study, urine was collected. The 3 HF groups were significantly heavier than the CON group. Muscle carnosine concentrations increased equally in the HFcar and HFba groups, while elevated plasma carnosine levels and carnosine-4-hydroxy-2-nonenal adducts were detected only in the HFcar group. Elevated plasma and urine N(ε)-(carboxymethyl)lysine in HF rats was reduced by ∼50% in the HFcar group but not in the HFba group. Likewise, inducible nitric oxide synthase mRNA was decreased by 47% (p < 0.05) in the HFcar group, but not in the HFba group, compared with HF rats. We conclude that plasma carnosine, but not muscle carnosine, is involved in preventing early-stage lipoxidation in the circulation and inflammatory signaling in the muscle of rats.

Complications With New Oral Anticoagulants Dabigatran and Rivaroxaban in Cutaneous Surgery.

BACKGROUND: Anticoagulant medications to date are not associated with increased risk of severe life-threatening complications during cutaneous surgery. Dabigatran and rivaroxaban are new orally administered anticoagulants that do not require laboratory monitoring and have no available specific antidotes, making perioperative management more complex. To the authors' knowledge, published data on the use of dabigatran or rivaroxaban in patients undergoing cutaneous surgery are limited. OBJECTIVE: The authors sought to study perioperative complications associated with dabigatran and rivaroxaban during cutaneous surgery. MATERIALS AND METHODS: Retrospective chart analysis was performed for all patients who underwent Mohs micrographic surgery or basic excision while taking dabigatran or rivaroxaban between January 1, 2010, and September 1, 2013, at Mayo Clinic, Rochester, MN. RESULTS: Twenty-seven patients taking dabigatran underwent 41 cutaneous surgeries, with only 1 mild bleeding complication observed that was remedied with a pressure dressing. Four patients on rivaroxaban underwent 5 cutaneous surgeries without complication. CONCLUSION: Because no patients on dabigatran or rivaroxaban experienced severe hemorrhagic complications during cutaneous surgery, a strategy of continuing these medically necessary medications during cutaneous surgery seems reasonable.

Efficacy of Dabigatran for Dissolving Deep Vein Thromboses in Outpatients With a Deteriorated General Condition.

Non-vitamin K antagonist oral anticoagulants (NOACs) have been widely used for the prevention of ischemic strokes in patients with nonvalvular atrial fibrillation (AF). At present, NOACs have been evaluated for the treatment of deep vein thrombosis (DVT). We examined the efficacy of dabigatran, the first NOAC for anticoagulation of AF in Japan, in outpatients who suffered from DVTs under a deteriorated general condition.Thirty-six consecutive outpatients diagnosed with DVT at our institute were enrolled. Not all patients could be hospitalized due to other clinical problems; 15 (42%) had malignant tumors, 9 (25%) psychological disorders, and 6 (17%) postoperative orthopedic disease. Dabigatran was administered at a dose of 110-150 mg once or twice daily, depending on the renal function and age. The mean dosage of dabigatran was 211.7 ± 36.6 mg per day. In 18 (50%) patients, the DVTs were completely dissolved and disappeared over a treatment term of 4.3 ± 4.3 months. In 9 patients (25%), the DVTs partly dissolved, but in the remaining 9 (25%) patients, dabigatran was totally ineffective. During a follow-up of 30.5 ± 5.3 months, DVTs did not recur with dabigatran in 18 patients with an effective efficacy. In a multivariate analysis, patients with small sized thromboses and those without malignant tumors were significantly associated with the DVTs dissolving (P = 0.003 and P = 0.006, respectively).Dabigatran was effective for dissolving DVTs in outpatients with a poor condition, particularly when the size of the DVT was small and malignant tumors were absent.

Perioperative Management of Dabigatran: A Prospective Cohort Study.

BACKGROUND: The perioperative management of dabigatran in clinical practice is heterogeneous. We performed this study to evaluate the safety of perioperative management of dabigatran using a specified protocol. METHODS AND RESULTS: Patients treated with dabigatran and planned for an invasive procedure were eligible for inclusion. The timing of the last dose of dabigatran before the procedure was based on the creatinine clearance and procedure-related bleeding risk. Resumption of dabigatran was prespecified according to the complexity of the surgery and consequences of a bleeding complication. Patients were followed up for 30 days for major bleeding (primary outcome), minor bleeding, arterial thromboembolism, and death. We included 541 cases: 324 procedures (60%) with standard risk of bleeding and 217 procedures (40%) with increased risk of bleeding. The last dose of dabigatran was at 24, 48, or 96 hours before surgery according to the protocol in 46%, 37%, and 6%, respectively, of the patients. Resumption was timed according to protocol in 77% with 75 mg as the first dose on the day of procedure in 40% of the patients. Ten patients (1.8%; 95% confidence interval, 0.7-3.0) had major bleeding, and 28 patients (5.2%; 95% confidence interval, 3.3-7.0) had minor bleeding events. The only thromboembolic complication was transient ischemic attack in 1 patient (0.2%; 95% confidence interval, 0-0.5), and there were 4 deaths unrelated to bleeding or thrombosis. Bridging was not used preoperatively but was administered in 9 patients (1.7%) postoperatively. CONCLUSION: Our protocol for perioperative management of dabigatran appears to be effective and feasible.

Risk of major bleeding in different indications for new oral anticoagulants: insights from a meta-analysis of approved dosages from 50 randomized trials.

BACKGROUND: A meta-analysis was performed to evaluate the risk of major bleeding with the use of New Oral Anticoagulants (NOACs). METHODS: Randomized controlled trials (RCTs) comparing NOACs (rivaroxaban, dabigatran, apixaban, edoxaban and darexaban) with comparators were selected. RESULTS: Fifty trials included 155,537 patients. Pooled analysis of all NOACs for all indications together demonstrated no significant difference between NOACs and comparators for risk of major bleeding (odds ratio [OR] 0.93, 95% CI 0.79-1.09). Pooled analysis also showed that NOACs caused significantly less major bleeding compared to vitamin K antagonists (VKA) (0.77, 0.64-0.91). The analysis for individual NOACs showed risk of major bleeding were not different with rivaroxaban, apixaban or dabigatran compared to pharmacologically active comparators or VKA. Indication specific analysis showed that NOACs were associated with significantly higher major bleeding after hip surgery (1.43, 1.02-1.99), in patients with acute coronary syndrome (ACS), (compared against placebo) (2.89, 2.01-4.14), and for medically ill patients (2.79, 1.69-4.60). For the treatment of acute venous thromboembolism (VTE) or pulmonary embolism (PE), NOACs were associated with significantly less bleeding (0.63, 0.44-0.90). No significant difference was found between NOACs and comparators in treatment of atrial fibrillation and for extended treatment of VTE. CONCLUSIONS: Risk of major bleeding with new oral anticoagulants varies with their indication for use. New agents may be associated with comparatively less major bleeding compared to VKA. NOAC may increase the risk of major bleeding after hip surgery, ACS and acute medically ill patients; but may be associated with less bleeding in treatment of acute VTE/PE.

Testing the therapeutic equivalence of novel oral anticoagulants for thromboprophylaxis in orthopedic surgery and for prevention of stroke in atrial fibrillation.

BACKGROUND: In studying the comparative effectiveness of novel oral anticoagulants (NOACs) in orthopedic surgery and in non-valvular atrial fibrillation, previous meta-analyses have found no proof of difference in head-to-head indirect comparisons between individual agents. However, the question of their therapeutic equivalence remains unanswered. OBJECTIVES: The objective of this analysis was to test the equivalence of three NOACs (dabigatran, rivaroxaban, apixaban) in orthopedic surgery and four NOACs (dabigatran, rivaroxaban, apixaban, and edoxaban) in non-valvular atrial fibrillation. METHODS: Standard pairwise meta-analysis and network meta-analysis for indirect comparisons were combined with equivalence testing. The endpoint was venous thromboembolism in orthopedic surgery and a composite of stroke or systemic embolism in atrial fibrillation. Comparisons were expressed as risk difference (RD). Margins for equivalence testing were derived from the original trials. RESULTS: Our results indicate that rivaroxaban and apixaban (but not dabigatran) are equivalent for thromboprophylaxis in orthopedic surgery. In atrial fibrillation, all the four NOACs we tested were found to meet the criterion of therapeutic equivalence. Some concern, however, is raised by some findings focused on adverse events of these agents, in which the equivalence was not proven in all analyses. CONCLUSIONS: Regardless of clinical implications, our results can be the basis to develop local acquisition tenderings on NOACS. In Italy, a new law has been issued according to which equivalence analyses have become a mandatory prerequisite for local tenderings.

Influence of dabigatran and rivaroxaban on routine coagulation assays. A nationwide Belgian survey.

The Belgian national External Quality Assessment Scheme performed a nationwide survey using lyophilised plasma samples spiked with dabigatran or rivaroxaban to demonstrate to the Belgian clinical laboratories how these drugs affect their routine coagulation assays prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen and antithrombin. Virtually all Belgian laboratories performing routine coagulation testing (189/192) participated in the survey. Both, dabigatran and rivaroxaban significantly prolonged the PT and aPTT in a concentration- and reagent-dependent manner. PT reagents were more influenced by rivaroxaban than by dabigatran and aPTT reagents more influenced by dabigatran than by rivaroxaban. Among PT reagents, Neoplastin R® was the most sensitive to rivaroxaban and Innovin® and Thromborel S® the least sensitive. Converting PT results to INR only increased the variability between reagents. Among aPTT reagents, Actin FSL® was the least sensitive to dabigatran while the other aPTT reagents showed slightly higher sensitivities. The presence of dabigatran led to falsely reduced fibrinogen concentrations when measured with a low thrombin concentration reagent. The presence of dabigatran caused an overestimation of the antithrombin level when measured with a thrombin-based activity assay and the presence of rivaroxaban an overestimation of the antithrombin level when measured with a FXa-based assay. Instrument-related differences were found for all tested parameters. In conclusion, this paper provides detailed information on the effect of dabigatran and rivaroxaban on routine coagulation assays as performed with a large number of reagent/instrument combinations.

[Laboratory assessment of haemostatic parameters in patients taking a direct thrombin inhibitor].

The problem of prevention and treatment of thromboembolic complications has a significant place in clinical practice for many years. The gold-standard agents in long-term protection from embologenic strokes, secondary prevention of venous thromboses and embolisms still remain vitamin K antagonists (in Russia - warfarin). However, despite high efficacy, administration of warfarin is fraught with dangers and associated with a series of inconveniences. A direct thrombin inhibitor, dabigatran etexilate (hereinafter referred to as dabigatran) was approved in the Russian Federation for prevention of thromboembolic complications in orthopaedic practice (2009), for prevention of ischaemic embologenic stroke in atrial fibrillation (2011) and for treatment of recurrent thrombosis of deep veins and pulmonary artery thromboembolism (2014). A characteristic feature of a therapeutic agent possessing an anticoagulation effect is correlation between intensity of hypocoagulation and haemorrhage. The effect of dabigatran on the laboratory parameters of haemostasis has been studied insufficiently, with no practical guidelines on assessing these alterations for prediction of the risk for haemorrhagic and thromboembolic complications. The present study included a total of 65 patients with non-valvular aetiology atrial fibrillation, taking dabigatran during from 6 to 18 months. All patients underwent laboratory assessment of the coagulation level and measuring blood coagulation activation markers in dynamics 10-14 days, 1, 6, 12 and 18 months after taking the agent. Thromboembolic and haemorrhagic risks were also assessed. It was revealed that administration of dabigatran leads to alterations in the main parameters of coagulogram. Determination of prothrombin (in % according to Quick's method) and activated partial thromboplastin time may be used for qualitative assessment of hypocoagulation. During the follow up period no statistically significant changes in the coagulation activation markers level were observed.