Discovery and biochemical characterization of two hexokinases from Crassostrea gigas.

Hexokinases (HKs) play a vital role in glucose metabolism, which controls the first committed step catalyzing the production of glucose-6-phosphate from glucose. Two HKs (CGIHK1 and CGIHK2) from the Pacific oyster Crassostrea giga were cloned and characterized. CGIHK1 and CGIHK2 were recombinantly expressed in Escherichia coli and successfully purified by the Ni-NTA column. The optimum pH of the two enzymes was pH 8.0 and 8.5, respectively. The optimum temperature of the two enzymes was 42 °C and 50 °C, respectively. Both enzymes showed a clear requirement for divalent magnesium and were strongly inhibited by SDS. CGIHK1 exhibited highly strict substrate specificity to glucose, while CGIHK2 could also catalyze other 11 monosaccharide substrates. This is the first report on the in vitro biosynthesis of glucose-6-phosphate by the hexokinases from Crassostrea gigas. The facile expression and purification procedures combined with different substrate specificities make CGIHK1 and CGIHK2 candidates for the biosynthesis of glucose-6-phosphate and other sugar-phosphates.

Evolution of antithrombotic therapy for patients with atrial fibrillation: The prospective global GLORIA-AF registry program.

OBJECTIVE: To assess baseline characteristics and antithrombotic treatment (ATT) prescription patterns in patients enrolled in the third phase of the GLORIA-AF Registry Program, evaluate predictors of treatment prescription, and compare results with phase II. METHODS: GLORIA-AF is a large, global, prospective registry program, enrolling patients with newly diagnosed nonvalvular atrial fibrillation (AF) at risk of stroke. Patients receiving dabigatran were followed for two years in phase II, and all patients were followed for 3 years in phase III. Phase II started when dabigatran became available; phase III started when the characteristics of patients receiving dabigatran became roughly comparable with those receiving vitamin K antagonists (VKAs). RESULTS: Between 2014 and 2016, 21,241 patients were enrolled in phase III. In total, 82% of patients were prescribed oral anticoagulation ([OAC]; 59.5% novel/nonvitamin K oral anticoagulants [NOACs], 22.7% VKAs). A further 11% of patients were prescribed antiplatelets without OAC and 7% were prescribed no ATT. A high stroke risk was the main driver of OAC prescription. Factors associated with prescription of VKA over NOAC included type of site, region, physician specialty, and impaired kidney function. CONCLUSION: Over the past few years, data from phase III of GLORIA-AF show that OACs have become the standard treatment option, with most newly diagnosed AF patients prescribed a NOAC. However, in some regions a remarkable proportion of patients remain undertreated. In comparison with phase II, more patients received NOACs in phase III while the prescription of VKA decreased. VKAs were preferred over NOACs in patients with impaired kidney function.

Dabigatran versus vitamin K antagonists for atrial fibrillation in clinical practice: final outcomes from Phase III of the GLORIA-AF registry.

BACKGROUND: Prospectively collected, routine clinical practice-based data on antithrombotic therapy in non-valvular atrial fibrillation (AF) patients are important for assessing real-world comparative outcomes. The objective was to compare the safety and effectiveness of dabigatran versus vitamin K antagonists (VKAs) in patients with newly diagnosed AF. METHODS AND RESULTS: GLORIA-AF is a large, prospective, global registry program. Consecutive patients with newly diagnosed AF and CHA2DS2-VASc scores ≥ 1 were included and followed for 3 years. To control for differences in patient characteristics, the comparative analysis for dabigatran versus VKA was performed on a propensity score (PS)-matched patient set. Missing data were multiply imputed. Proportional-hazards regression was used to estimate hazard ratios (HRs) for outcomes of interest. Between 2014 and 2016, 21,300 eligible patients were included worldwide: 3839 patients were prescribed dabigatran and 4836 VKA with a median age of 71.0 and 72.0 years, respectively; > 85% in each group had a CHA2DS2-VASc-score ≥ 2. The PS-matched comparative analysis for dabigatran and VKA included on average 3326 pairs of matched initiators. For dabigatran versus VKAs, adjusted HRs (95% confidence intervals) were: stroke 0.89 (0.59-1.34), major bleeding 0.61 (0.42-0.88), all-cause death 0.78 (0.63-0.97), and myocardial infarction 0.89 (0.53-1.48). Further analyses stratified by PS and region provided similar results. CONCLUSIONS: Dabigatran was associated with a 39% reduced risk of major bleeding and 22% reduced risk for all-cause death compared with VKA. Stroke and myocardial infarction risks were similar, confirming a more favorable benefit-risk profile for dabigatran compared with VKA in clinical practice. Clinical trial registration https://www. CLINICALTRIALS: gov . NCT01468701, NCT01671007.

Changes in anticoagulant prescription patterns over time for patients with atrial fibrillation around the world.

BACKGROUND: Prescribing patterns for stroke prevention in atrial fibrillation (AF) patients evolved with approval of non-Vitamin K antagonist oral anticoagulants (NOACs) over time. OBJECTIVES: To assess changes in anticoagulant prescription patterns in various geographical regions upon first approval of a NOAC and to analyze the evolution of oral anticoagulants (OACs) use over time in relation to CHA2DS2-VASc and HAS-BLED risk profiles. METHODS: Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) Phases II and III reported data on antithrombotic therapy for patients with newly diagnosed AF and ≥1 stroke risk factor. We focused on sites enrolling patients in both phases and reported treatment patterns for the first 4 years after initial NOAC approval. RESULTS: From GLORIA-AF Phases II and III, 27 432 patients were eligible for this analysis. When contrasting the first year with the fourth year of enrolment, the proportion of NOAC prescriptions increased in Asia from 29.2% to 60.8%, in Europe from 53.4% to 75.8%, in North America from 49.0% to 73.9% and in Latin America from 55.7% to 71.1%. The proportion of Vitamin K antagonists (VKAs) use decreased across all regions over time, in Asia from 26.0% to 9.8%, in Europe from 35.5% to 16.8%, in North America from 28.9% to 12.1%, and in Latin America from 32.4% to 17.8%. In the multivariable analysis, factors associated with NOAC prescription were as follows: enrolment year, type of site, region, stroke and bleeding risk scores, and type and categorization of AF. CONCLUSIONS: During 4 years after the approval of the first NOAC, NOAC use increased, while VKA use decreased, across all regions.

Atrial fibrillation and comorbidities: Clinical characteristics and antithrombotic treatment in GLORIA-AF.

BACKGROUND: Patients with AF often have multimorbidity (the presence of ≥2 concomitant chronic conditions). OBJECTIVE: To describe baseline characteristics, patterns of antithrombotic therapy, and factors associated with oral anticoagulant (OAC) prescription in patients with AF and ≥2 concomitant, chronic, comorbid conditions. METHODS: Phase III of the GLORIA-AF Registry enrolled consecutive patients from January 2014 through December 2016 with recently diagnosed AF and CHA2DS2-VASc score ≥1 to assess the safety and effectiveness of antithrombotic treatment. RESULTS: Of 21,241 eligible patients, 15,119 (71.2%) had ≥2 concomitant, chronic, comorbid conditions. The proportions of patients with multimorbidity receiving non-vitamin K antagonist oral anticoagulants (NOACs) and vitamin K antagonists (VKA) were 60.2% and 23.6%, respectively. The proportion with paroxysmal AF was 57.0% in the NOAC group and 45.4% in the VKA group. Multivariable log-binomial regression analysis found the following factors were associated with no OAC prescription: pattern of AF (paroxysmal, persistent, or permanent), coronary artery disease, myocardial infarction, prior bleeding, smoking status, and region (Asia, North America, or Europe). Factors associated with OAC prescriptions were age, body mass index, renal function, hypertension, history of cerebral ischemic symptoms, and AF ablation. CONCLUSION: Multimorbid AF patients prescribed NOACs have fewer comorbidities than those prescribed VKAs. Age, AF pattern, comorbidities, and renal function are associated with OAC prescription.

Anticoagulation Prescription and Outcomes in Relation to Renal Function in Patients with Atrial Fibrillation: Results from GLORIA-AF.

Objective Anticoagulation management in patients with atrial fibrillation (AF) and impaired renal function is challenging. This study aimed to evaluate anticoagulation prescription patterns in relation to renal function and to describe 2-year clinical outcomes among dabigatran users. Methods Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) is an international, prospective, and observational study program involving patients with newly diagnosed AF at risk for stroke. Prescription patterns were assessed by creatinine clearance (CrCl) at enrollment. Dabigatran users were followed for 2 years. Clinical outcomes were standardized for stroke and bleeding risk, based on CHA 2 DS 2 -VASc and HAS-BLED scores, with missing values imputed. Results Baseline CrCl values were available for 12,056 of 15,308 eligible patients (79%). With declining renal function, prescriptions increased for vitamin K antagonists (VKAs) and decreased for dabigatran (30-47% and 34-12%, respectively). The prescription of other non-vitamin K antagonists remained similar across CrCl groups (14-19%). In 4,873 dabigatran users, standardized stroke rates were low across all CrCl groups; 0.58/100 patient-years (95% confidence interval [CI]: 0.30-0.90) in CrCl ≥80 mL/min, 0.85 (95% CI: 0.48-1.21) in CrCl 50 to 79 mL/min, and 0.33 (95% CI: 0.06-1.11) in CrCl 30 to 49 mL/min. Similarly, major bleeding rates were low and numerically increased with declining renal function (0.68/100 patient-years, 95% CI: 0.39-1.03; 0.92, 95% CI: 0.58-1.32; and 1.26, 95% CI: 0.66-1.97, respectively). Conclusion In patients with AF, VKA prescriptions increased and dabigatran prescriptions decreased with declining renal function. Rates of stroke and major bleeding in dabigatran patients remained low across the categories of renal impairment.

Characteristics and 2-year outcomes of dabigatran treatment in patients with heart failure and atrial fibrillation: GLORIA-AF.

AIMS: This study aimed to describe baseline characteristics of patients with atrial fibrillation (AF) at risk of stroke with and without history of heart failure (HF) and report 2-year outcomes in the dabigatran-treated subset of a prospective, global, observational study (GLORIA-AF). METHODS AND RESULTS: Newly diagnosed patients with AF and CHA2 DS2 -VASc score ≥ 1 were consecutively enrolled. Baseline characteristics were assessed by the presence or absence of HF diagnosis at enrolment. Incidence rates for outcomes in dabigatran-treated patients were estimated with and without standardization by stroke (excluding HF component) and bleeding risk scores. A total of 15 308 eligible patients were enrolled, including 15 154 with known HF status; of these, 3679 (24.0%) had been diagnosed with HF, 11 475 (75.0%) had not. Among 4873 dabigatran-treated patients, 1169 (24.0%) had HF, and 3658 (75.1%) did not; the risk of stroke was high (CHA2 DS2 -VASc score ≥ 2) for 94.3% of patients with HF and 85.8% without, while 6.0% and 7.0%, respectively, had a high bleeding risk (HAS-BLED ≥ 3). Incidence rates of all-cause death in dabigatran-treated patients with and without HF, standardized for CHA2 DS2 -VASc and HAS-BLED scores, were 4.76 vs. 1.80 per 100 patient years (py), with roughly comparable rates of stroke (0.82 vs. 0.60 per 100 py) and major bleeding (1.20 vs. 0.92 per 100 py). CONCLUSIONS: Patients with AF and history of HF may have greater disease burden at AF diagnosis and increased mortality rates vs. patients without HF. Stroke and major bleeding rates were roughly comparable between groups confirming the long-term safety and effectiveness of dabigatran in patients with HF.

Persistence with Anticoagulation for Atrial Fibrillation: Report from the GLORIA-AF Phase III 1-Year Follow-up.

BACKGROUND: We aimed to assess the extent to which drug persistence is better with non-vitamin K antagonist oral anticoagulants (NOACs) than vitamin K antagonists (VKAs) in atrial fibrillation (AF) patients and to estimate the difference in therapy persistence depending on NOAC dosing regimen (once daily (QD) vs. twice daily (BID)). METHODS: Consecutive patients were followed for 1 year in phase III of the GLORIA-AF registry. Drug persistence was defined as the use of OAC without any discontinuation in >30 days or switching to alternative therapy. RESULTS: Among 21,109 eligible patients in phase III, 17,266 patients who were prescribed OAC at baseline and those who took ≥1 OAC dose were included. The 1-year proportion of patients receiving NOAC and VKA who persisted on treatment was 80% and 75%, respectively. The 1-year persistence with NOACs BID and NOACs QD was 81% and 80%, respectively. Female gender, hypertension, older age, alcohol use, permanent, asymptomatic, and minimally symptomatic AF were associated with better OAC persistence. Region, medication usage predisposing to bleeding, being a current smoker, treatment reimbursement, and proton pump inhibitors were associated with lower OAC persistence. CONCLUSIONS: Drug persistence was higher with NOACs (1-year persistence was 80%) than with VKAs (75%). There was little difference in 1-year persistence between NOAC dosing regimens.

Stroke prevention in atrial fibrillation changes after dabigatran availability in China: The GLORIA-AF registry.

BACKGROUND: Until the approval of dabigatran etexilate, treatment choices for stroke prevention in patients with atrial fibrillation (AF) were vitamin K antagonists (VKAs) or antiplatelet drugs. This analysis explored whether availability of non-vitamin K antagonist oral anticoagulants post-dabigatran approval was associated with changing treatment patterns in China. METHODS: Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) collected data on antithrombotic therapy choices for patients with newly diagnosed nonvalvular AF at risk for stroke. In China, enrollment in phase 1 (before dabigatran approval) and phase 2 (after dabigatran approval) occurred from 2011 to 2013 and 2013 to 2014, respectively. Analyses were restricted to sites within China that contributed patients to both phases. The weighted average of the site-specific results was estimated for standardization. Sensitivity analyses used multiple regression. RESULTS: Thirteen sites participated in both phase 1 (419 patients) and phase 2 (276 patients), 76.1% and 16.0% were known to be at high risk for stroke (CHA2DS2-VASc ≥2) and bleeding (HAS-BLED ≥3); 55.5% were male. In phase 1, 16.7%, 61.6%, and 21.7% of patients were prescribed oral anticoagulants (OACs), antiplatelet agents, and no treatment, respectively. Respective proportions were 26.4%, 40.6%, and 33.0% in phase 2. The absolute increase in the site-standardized proportion of patients prescribed OACs after dabigatran availability was 9.9% (95% confidence interval [CI]: 3.7%-16.0%). There was a standardized 17.3% (95% CI: -24.3% to -10.4%) absolute decrease in antiplatelet agent use. CONCLUSIONS: There was an increase in OAC and decrease in antiplatelet agent prescription since dabigatran availability in China. However, a large proportion of AF patients at risk for stroke remained untreated.

Influence of BMI and geographical region on prescription of oral anticoagulants in newly diagnosed atrial fibrillation: The GLORIA-AF Registry Program.

OBJECTIVE: To investigate the association between body mass index (BMI) and oral anticoagulant (OAC) prescription in atrial fibrillation (AF). METHODS: Patients with newly diagnosed non-valvular AF (<3 months) with ≥1 stroke risk factors enrolled in the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) in Asia, Europe and North America were evaluated. RESULTS: The cohort (n = 13,793) comprised patients from all BMI categories (kg/m2): 1.4% were underweight (<18.5), 27.3% had a normal BMI (18.5 to <25), 37.9% were overweight (25 to <30), 19.3% were moderately obese (30 to <35), and 12.7% were morbidly obese (≥35). The highest proportion of Asians had a BMI of 18.5 to <25 kg/m2, while the highest proportion of patients from Europe and North America were overweight and a substantial proportion of North Americans morbidly obese. In the multivariable analysis, the probability ratio of non-prescription of OAC, as compared to normal BMI, decreased for overweight (RR = 0.907), moderately obese (RR = 0.802) and severe very severe obese patients (RR = 0.659). Moreover, the probability ratio of non-prescription of OACs was increased in the Asia or North America regions, as compared with Europe, in patients aged <65 years or female patients, as well as in patients with prior bleeding or vascular disease. CONCLUSIONS: The distribution of BMI differed among the continents. An increased BMI was associated with a lower probability of non-prescription of OACs, as compared with a normal BMI. The probability of non-prescription of OACs was increased in the Asia or North America regions, as compared with Europe.

Antithrombotic treatment for newly diagnosed atrial fibrillation in relation to patient age: the GLORIA-AF registry programme.

AIMS: To assess antithrombotic therapy choices in relation to patient age in a large, global registry on atrial fibrillation (AF). METHODS AND RESULTS: Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) is an international programme involving patients with newly diagnosed AF and ≥1 risk factors for stroke. We used Phase II data (from November 2011 through December 2014), which commenced immediately following first non-vitamin K antagonist oral anticoagulants (NOACs) approval in participating countries. Of 15 092 patients (mean age 70.5 ± 11.0 years), enrolled at 982 centres, 26.9% were aged <65 years, 33.9% 65-74, 30.5% 75-84, and 8.6% ≥85 years old. Oral anticoagulant (OAC) use was 73.5%, 81.4%, 83.3%, and 82.3% (overall NOACs use was 44.4%, 49.7%, 48.7%, and 45.6%) for those aged <65, 65-74, 75-84 and ≥85 years, respectively. Corresponding proportions for antiplatelet monotherapy and no treatment were: 16.2% and 10.2%; 11.2% and 7.3%; 10.0% and 6.5%; 10.5% and 7.0%, respectively. Of those aged 65-74, 75-84, and ≥85 years, respectively, 83.7, 86.8 and 85.4% received OAC unless bleeding risk was high (HAS-BLED ≥3), whereby 64.1%, 63.5%, and 64.5% were anticoagulated, and 31.1%, 30.3%, and 31.3% received antiplatelets only. Of patients ≥85 years, OAC use was 88.1% in Europe (NOAC 45.1%), 79.5% in North America (NOAC 44.8%), and 54.1% in Asia (NOAC 40.2%). CONCLUSION: Despite geographic differences in OAC use, neither OAC nor NOAC uptake was lower for patients ≥85 years old compared with younger patients. Although the majority of patients was prescribed OAC at all ages, nearly one-third received antiplatelet monotherapy when bleeding risk was increased. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT01468701.

Dabigatran Persistence and Outcomes Following Discontinuation in Atrial Fibrillation Patients from the GLORIA-AF Registry.

Prospective studies evaluating persistence to nonvitamin K antagonist oral anticoagulants in patients with atrial fibrillation are needed to improve our understanding of drug discontinuation. The study objective was to evaluate if and when patients with newly diagnosed atrial fibrillation stop dabigatran treatment and to report outcomes following discontinuation. Patients prescribed dabigatran in diverse clinical practice settings were consecutively enrolled and followed for 2 years. Dabigatran persistence over time, reasons for discontinuation, and outcomes post discontinuation were assessed. Of 4,859 patients, aged 70.2 ± 10.4 years, 55.7% were male. Overall 2-year dabigatran persistence was 70.9% (95% confidence interval [CI] 69.6 to 72.2). Persistence probability was lower in the first 6-month period (83.7% [82.7 to 84.8]) than in subsequent periods for patients on dabigatran at the start of each period (6 to 12 months, 92.5% [91.6 to 93.3]; 12 to 18 months, 95.1% [94.3 to 95.8]; 18 to 24 months, 96.3% [95.6 to 96.9]). Of 1,305 patients (26.9%) who discontinued dabigatran, adverse events were reported as the reason for discontinuation in 457 (35.0%). Standardized stroke incidence rate post discontinuation (per 100 patient-years) in patients discontinuing without switching to another oral anticoagulant was 1.76 (95% CI 0.89 to 2.76) and 1.02 (95% CI 0.43 to 1.76) in those who switched, consistent with the expected benefit of remaining on treatment. Patients persistent with treatment at 1 year had >90% probability of remaining persistent at 2 years suggesting clinical interventions to improve persistence should be focused on the early period following treatment initiation.

Safety and effectiveness of dabigatran at 2 years: Final outcomes from Phase II of the GLORIA-AF registry program.

GLORIA-AF is a large, ongoing, prospective, global registry program run in 3 phases, assessing long-term safety and effectiveness of dabigatran etexilate (dabigatran) in patients with newly diagnosed atrial fibrillation (AF) in clinical practice. This report provides the final analysis of 2-year clinical outcomes of the full cohort of 4873 patients prescribed dabigatran and followed for a mean of 18.0 +/- 9.4 months out of the 15,308 eligible patients enrolled in Phase II (2011-2014). The overall incidence rates per 100 person-years were: stroke 0.65 (95% CI 0.48-0.87), major bleeding 0.97 (0.76-1.23) and myocardial infarction (MI) 0.50 (0.35-0.69), with observed event rates broadly consistent in all study regions, which confirms the sustained safety and effectiveness of dabigatran over 2 years of observation in clinical practice.

Transcriptomic Study Reveals Recovery of Impaired Astrocytes Contribute to Neuroprotective Effects of Danhong Injection Against Cerebral Ischemia/Reperfusion-Induced Injury.

Danhong Injection (DHI) is widely used in clinics for treating cardiovascular and cerebrovascular diseases in China. However, the mode of action of DHI for neuroprotection remains unclear. In the present study, we deemed to investigate the effects of DHI on a rat model of cerebral ischemia/reperfusion injury (IRI) with an emphasis on its regulated gene profile obtained from microarray assays. Firstly, we showed that a 14-day DHI treatment effectively ameliorated severity of neurological deficits, reduced size of ischemic damage, improved status of oxidation stress, as well as systemic inflammation for IRI rats, along with which was a pronounced reduced cell infiltration in the area of periaqueductal gray matter. Secondly, bioinformatic analyses for the 429 differentially expressed genes (DEGs) regulated by DHI treatment pointed out ECM-receptor interaction, neuroactive ligand-receptor interaction, and endocytosis as the top three biological processes, while Toll-like recptor 4 (TLR4) as the most relavant singaling molecule. Lastly, we provided evidences showing that DHI might directly protect primary astrocytes from oxygen and glucose deprivation/re-oxygenation (OGD/Re) injury, the effects of which was associated with LAMC2 and ADRB3, two DEGs related to the top three biological processes according to transcriptomic analysis. In conlusion, we reported that DHI might work through maintaining the integrity for brain-blood barrier and to regulate TLR4-related signaling pathway to diminish the inflammation, therefore, effectively improved the outcomes of IRI. Our findings suggested that the attenuated astrocytic dysfunction could be a novel mechanism contributing to the neuroprotective effects of DHI against cerebral ischemia/reperfusion-induced damage.

Gender Differences in Antithrombotic Treatment for Newly Diagnosed Atrial Fibrillation: The GLORIA-AF Registry Program.

AIMS: Data on gender differences in oral anticoagulation for stroke prevention in patients with atrial fibrillation are conflicting, largely limited to regional reports and vitamin K antagonist use. We aimed to analyze gender-specific anticoagulant prescription patterns early following the introduction of non-vitamin K antagonist oral anticoagulants (NOACs) in a large, global registry on atrial fibrillation. METHODS: The Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) is an international registry program involving patients with newly diagnosed atrial fibrillation (<3 months from arrhythmia onset). We used data from 15,092 consecutive patients (median age, 71.0 years; 45.5% were women) enrolled between 2011 and 2014. Globally, 79.7% of women and 80.2% of men were anticoagulated; the absolute between-gender difference in prevalence of anticoagulant use was -0.5% (95% confidence interval, -1.8% to 0.8%). Vitamin K antagonists were prescribed to 32.8% and 31.9% (NOACs 46.8% and 48.3%) of women and men, respectively. RESULTS: No confounder for the association between gender and anticoagulant prescription was identified. Between-gender differences in anticoagulant use (lower use in women compared with men by decreasing order of magnitude of the difference) were found for CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65-74 years, sex category [female]) score = 1; CHADS2 (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke) score = 0; previous bleeding; age <65 years; no history of hypertension; myocardial infarction; coronary artery disease; North America region; and specialist office setting. CONCLUSION: Globally, the prevalence of anticoagulant use is similar in women and men. The decision to prescribe oral anticoagulation seems to depend predominantly on guideline-related differences in stroke risk stratification rather than on gender.

Two-year follow-up of patients treated with dabigatran for stroke prevention in atrial fibrillation: Global Registry on Long-Term Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) registry.

BACKGROUND AND PURPOSE: GLORIA-AF is a large, global, prospective registry program of newly diagnosed atrial fibrillation (AF) patients with ≥1 stroke risk factors. We describe the effectiveness and safety of dabigatran etexilate over 2 years from routine clinical practice in nearly 3000 patients from GLORIA-AF who are newly diagnosed with non-valvular AF and at risk of stroke. METHODS: Consecutive enrollment into phase II of GLORIA-AF was initiated following approval of dabigatran for stroke prevention in non-valvular AF. Within this Phase II, 2937 dabigatran patients completed 2-year follow-up by May 2016 and were eligible for analysis. Patients who took at least 1 dose of dabigatran (n=2932) were used to estimate incidence rates. RESULTS: Overall incidence rates per 100 person-years of 0.63 (95% confidence interval [CI], 0.42-0.92) for stroke, 1.12 (0.83-1.49) for major bleeding, 0.47 (0.29-0.72) for myocardial infarction, and 2.69 (2.22-3.23) for all-cause death were observed. For patients taking 150 mg dabigatran twice daily (BID), corresponding rates (95% CI) were 0.56 (0.30-0.94), 1.00 (0.64-1.47), 0.48 (0.25-0.83), and 2.07 (1.55-2.72), respectively. For patients taking 110 mg dabigatran BID, event rates (95% CI) were 0.67 (0.33-1.20), 1.16 (0.70-1.80), 0.43 (0.17-0.88), and 3.16 (2.36-4.15). CONCLUSIONS: These global data confirm the sustained safety and effectiveness of dabigatran over 2 years of follow-up, consistent with the results from clinical trials as well as contemporary real-world studies. WHAT IS KNOWN: • Non-vitamin K antagonist (VKA) anticoagulants (NOACs) are the preferred therapy for prevention of ischemic stroke based on phase 3 trials, but there is insufficient information on their efficacy and safety in daily practice, based on prospectively collected data. WHAT IS NEW: • This study shows that in non-valvular AF patient population, with up to 2 years of follow-up, the use of dabigatran led to a low incidence of ischemic stroke, major bleeding, and myocardial infarction in routine clinical care, confirming the sustained safety and effectiveness of dabigatran in clinical practice over 2 years of follow-up.

Stroke-prevention strategies in North American patients with atrial fibrillation: The GLORIA-AF registry program.

BACKGROUND: Antithrombotic prophylaxis with oral anticoagulation (OAC) substantially reduces stroke and mortality in patients with atrial fibrillation (AF). HYPOTHESIS: Analysis of data in the Global Registry on Long-Term Antithrombotic Treatments in Patients With Atrial Fibrillation (GLORIA-AF), an international, observational registry of patients with newly diagnosed AF, can identify factors associated with treatment decisions and outcomes. METHODS: Multivariable regression identified patient, physician, and temporal factors associated with OAC prescription, compared with management with antiplatelet drugs or no antithrombotic drugs in North American patients enrolled between November 2011 and February 2014. RESULTS: Of 3320 eligible patients (mean age, 71 ± 11 years; 1879 males with CHA2 DS2 -VASc ≥1 and 1441 females with CHA2 DS2 -VASc ≥2), 79.3%, 12.5%, and 7.4% received OAC, antiplatelet drugs, or no antithrombotic therapy, respectively. Of those prescribed OAC, 66.4% received non-vitamin K antagonist oral anticoagulation and 24.5% received concomitant therapy with antiplatelet drugs. Independent predictors of OAC therapy were nonparoxysmal AF (odds ratio, 95% confidence interval: 2.02, 1.56-2.63), prior stroke/transient ischemic attack (2.00, 1.37-2.92), specialist care (1.50, 1.04-2.17), more concomitant medications (1.47, 1.13-1.92), commercial insurance (1.41, 1.07-1.85), and heart failure (1.44, 1.07-1.92). Antiplatelet drugs (0.18, 0.14-0.23), prior falls (0.41, 0.27-0.63), and prior bleeding (0.50, 0.35-0.72) were inversely associated with OAC prescription. CONCLUSIONS: In GLORIA-AF, 20% of the population comprising males with CHA2 DS2 -VASc ≥1 and females with CHA2 DS2 -VASc ≥2 did not receive OAC therapy. Patient characteristics associated with a lower likelihood of OAC prescription were use of antiplatelet drugs, paroxysmal pattern of AF, history of falls, and prior bleeding.

Investigation of the reverse effect of Danhong injection on doxorubicin-induced cardiotoxicity in H9c2 cells: Insight by LC-MS based non-targeted metabolomic analysis.

Although Danhong injection (DHI) has been clearly shown to attenuate ischemic myocardial injury and improve heart function, there is no research regarding its role in doxorubicin (DOX)-induced cardiomyopathy. In this study, we aimed to investigate the reverse effect of DHI on DOX-induced cardiotoxicity in H9c2 cells. The results of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay demonstrated that DHI had no cytotoxicity towards the relevant cell line unless the concentration was as high as 50 µL/mL. The satisfactory cardioprotective effect of DHI exerted at the concentration of 10 µL/mL, which agreed well with the result of real-time cell viability assay. Then non-targeted metabolomics based on LC-MS was employed to characterize metabolic alterations in DOX-induced cells with DHI treatment. Multivariate analysis, including PCA and PLS-DA, revealed 31 altered metabolites after DOX treatment that were primarily related to the disturbance of amino acids and nucleotides metabolism. While DHI could intervene in some disturbed metabolic pathways, such as the metabolism of arginine, glutathione (GSH), pantothenic acid, cytidine, inosine and 5'-methylthioadenosine. These results suggested that DHI exerted the therapeutic effect by improving energy metabolism and attenuating oxidative stress. The present study can lay a foundation for further research on the promising therapeutic effect of DHI in managing DOX-induced cardiotoxicity.

Regional Differences in Antithrombotic Treatment for Atrial Fibrillation: Insights from the GLORIA-AF Phase II Registry.

Introduction Although guideline-adherent antithrombotic therapy (ATT) for stroke prevention in atrial fibrillation (AF) is associated with lower mortality and thromboembolism, ATT uptake shows geographic variation worldwide. We aimed to assess thromboembolic risk and baseline ATT by geographic region and identify factors associated with prescription of ATT in a large, truly global registry of patients with recently diagnosed AF. Methods and Results Our analysis comprises 15,092 patients newly diagnosed with non-valvular AF at risk for stroke, enrolled in Phase II of Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF). Global oral anticoagulation (OAC) use was 79.9%, being highest in Europe (90.1%), followed by Africa/Middle East (87.4%) and Latin America (85.3%), North America (78.3%) and Asia (55.2%). Among OAC users, vitamin K antagonists (VKAs) have been replaced by non-VKA OACs (NOACs) as the more prevalent OAC option in all regions, with highest use in North America (66.5%) and lowest in Asia (50.2%). In Asia, OAC was 80.4% in community hospitals but only 49.8% in university hospitals and 42.6% in specialist offices, and varied from 21.0% in China to 89.7% in Japan (NOACs at 5.8% in China and 83.3% in Japan). Globally, 76.5% of low-risk patients were prescribed ATT (46.1% OAC), whereas 17.7% high-risk patients were not anticoagulated (Europe 8.8%; North America 18.9%; Asia 42.4%). Conclusion Substantial inter- and intra-regional differences in ATT for stroke prevention in AF are evident in this global registry. While guideline-adherent ATT can be further improved, NOACs are the main contributor to high OAC use worldwide.

Persistence With Dabigatran Therapy at 2 Years in Patients With Atrial Fibrillation.

BACKGROUND: Guidelines recommend long-term oral anticoagulation therapy for stroke prevention in patients with atrial fibrillation (AF). Treatment discontinuation rates in vitamin K antagonist (VKA)-treated patients are high but may be lower with non-VKA oral anticoagulant agents. OBJECTIVES: The goal of this study was to describe and explore predictors of dabigatran etexilate persistence in patients with newly diagnosed AF over 2 years of follow-up. METHODS: Consecutive patients newly diagnosed with AF and ≥1 stroke risk factor were followed up for 2 years. Dabigatran nonpersistence was defined as discontinuation of dabigatran for >30 days. A multivariable Cox regression model included region as well as patient clinical and sociodemographic characteristics to explore predictors of nonpersistence. RESULTS: Eligible patients (N = 2,932) took ≥1 dabigatran dose; their mean age was 70.3 ± 10.2 years, and 55.3% were male. The 2-year probability of dabigatran persistence was 69.2%. Approximately 7% switched to a factor Xa inhibitor and 6% to a VKA. Approximately one-third of dabigatran discontinuations were primarily due to serious or nonserious adverse events. Patients from North America had the highest discontinuation risk, and Latin America had the lowest. Minimally symptomatic or asymptomatic AF and permanent AF were associated with a lower risk for dabigatran nonpersistence. Previous proton pump inhibitor use was associated with a higher risk for dabigatran nonpersistence. CONCLUSIONS: Probability of treatment persistence with dabigatran after 2 years was approximately 70%. Nearly one-half of the patients who stopped dabigatran switched to another oral anticoagulant agent. Patients from North America, and those with paroxysmal, persistent, or symptomatic AF, may be at a higher risk for discontinuing dabigatran.