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.

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.

Reversal strategies and outcomes in patients with atrial fibrillation and warfarin-associated intracranial hemorrhage.

PURPOSE: Evaluate reversal strategies in atrial fibrillation (AF) patients with warfarin-associated intracranial hemorrhage (ICH) in clinical care. MATERIALS AND METHODS: Observational cohort of AF patients with warfarin-associated ICH at two referral hospitals (2007-2010), with patient features, reversal agents, and outcomes collected from medical records. RESULTS: Among 498 ICH patients 403 received fresh frozen plasma (FFP) without 3-factor prothrombin complex concentrates (PCCs) or recombinant factor VIIa (rFVIIa), 65 received PCCs or rFVIIa, mostly with FFP, and 30 received no acute reversal agents. Median time from presentation to reversal agent administration was 3.4 h (IQR 2.3-5.3). INR was reversed to ≤1.4 by 6 h post-presentation in 46% of patients receiving PCCs/rFVIIa versus 15% receiving FFP alone (p<0.0001). Among PCCs/rFVIIa recipients, 31% died in-hospital vs. 24% receiving FFP alone (p=0.27). Adjusted OR for death accounting for age and Glasgow Coma Score was 0.78 (0.36-1.69) for PCCs/rFVIIa vs FFP only and 1.16 (0.59-2.27) comparing those reaching vs. not reaching INR ≤ 1.4 at 6 h. CONCLUSIONS: Treatment with PCCs/rFVIIa led to faster INR reversal than treatment with FFP alone. Neither treatment with PCCs/rFVIIa nor rapid INR reversal was associated with improved survival. Delays receiving PCCs may largely eliminate the benefit of treatment.

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.

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.

Global Use of Idarucizumab in Clinical Practice: Outcomes of the RE-VECTO Surveillance Program.

Idarucizumab was approved for the reversal of dabigatran in 2015. We investigated whether postapproval usage patterns of idarucizumab in a real-world setting reflect those observed in the pivotal trials. No safety or efficacy data were collected in this medical record-based observational study. RE-VECTO, a global postapproval, international, surveillance program, involved hospital pharmacies in countries where idarucizumab was licensed and dispensed (August 2016-June 2018). Characteristics of sites prescribing idarucizumab and of eligible patients (≥ 18 years old and receiving idarucizumab regardless of prior oral anticoagulant use), as well as idarucizumab utilization data, were collected and analyzed descriptively. Sixty-one sites enrolled 359 patients. Most pharmacies (85.2%) were centralized, and the median idarucizumab units stocked per hospital was 2.0 (interquartile range, 1.0-3.0). Almost three-quarters of patients were elderly (74.9% aged > 70 years), and only four (1.1%) had received idarucizumab before. Nearly all patients were treated with dabigatran (97.5%). There was a low frequency of unapproved dabigatran dosage regimens (3.3%). Life-threatening or uncontrolled bleeding was the most frequent indication for idarucizumab (57.7%), followed by emergency surgery/urgent procedure (35.9%). Of the life-threatening bleeding events, the most frequent were gastrointestinal tract (44.4%) and intracranial (38.6%). Most patients (95.0%) were given the full dose of two vials (2 × 2.5 g) of idarucizumab initially, and very few (1.7%) received a second dose. Of those patients requiring emergency or scheduled/planned surgery/procedures, 25.5% underwent gastrointestinal and/or abdominal surgery/procedures. Real-world usage patterns of idarucizumab provide valuable insights into emergency reversal strategies. Off-label use was minimal.

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.

Claims Data Studies of Direct Oral Anticoagulants Can Achieve Balance in Important Clinical Parameters Only Observable in Electronic Health Records.

Claims databases provide information on the effects of direct oral anticoagulants (DOACs) as used in routine care but may not contain important data on clinical characteristics, which may be captured in electronic health records (EHRs). Within a US claims database, we identified patients initiating a DOAC or warfarin between October 2010 and December 2014. Propensity score (PS) matching, 1:1, was used to balance 78 claims-defined baseline characteristics. We evaluated whether balance was achieved in patient characteristics immeasurable in the claims data study by evaluating the balance in clinical information (using absolute standardized differences (aSDs)) from linked EHR data. From a claims data cohort study of 140,187 patients, 5,935 (4.2%) were linked to EHR data. After PS matching, almost all EHR-defined patient characteristics were well balanced (aSD < 0.1). A new user active comparator design with 1:1 PS matching on many patient characteristics improved balance on clinical risk factors observed in EHRs but not in claims data.

Symptomatology long-term evolution after hospitalization for anorexia nervosa: Drive for thinness to explain effects of body dissatisfaction on type of outcome.

Anorexia nervosa (AN) is a serious psychiatric disorder associated with the highest mortality rate. Body dissatisfaction (BD) is now considered as an important risk factor for AN onset and relapse. Recent results lead to the hypothesis according to which AN and drive for thinness (DT) are related to body dissatisfaction. The primary aim of this current study was to identify whether DT mediated the relationship between BD and AN symptoms several years after hospitalization. As a secondary aim, self-reported Body Shape Questionnaire, Eating Attitude Test, Eating Disorder Inventory and Beck Depression Inventory scores were compared between the 48 women with a history of severe AN and 73 matched controls. A mediation analysis didn't show evidence of a direct effect of BD on eating disorder symptomatology after controlling for DT suggesting a full mediation of DT on the association between BD and eating disorders symptomatology. Results also showed that patients with a bad outcome had a higher score of DT than controls, which was not the case of patients with a good outcome. These findings highlight the potential importance of DT and the usefulness of targeting this dimension in therapeutic interventions for AN patients if further research confirm these results.

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.

Contribution of modeling approaches and virtual populations in transposing the results of clinical trials into real life and in enlightening public health decisions.

Modeling consists in aggregating separate pieces of knowledge, according to a given structure and rules. It allows studying the behavior of more or less complex systems by simulation techniques. Modeling is used in different state-of-the-art technological domains (meteorology, aeronautics). Its use has grown for the evaluation of medicines and medical devices, from conception to prescription (marketing authorization, reimbursement, price setting and re-registrations). It follows a scientific approach and is the object of good practice recommendations. Coupling models to virtual populations allows obtaining realistic results at the population level, testing diagnostic or therapeutic strategies, as well as estimating the consequences of transposing the results of clinical trials to the population. Through examples, the participants of the Round Table analyzed the contributions of the coupling of models and realistic virtual populations, and proposed guidelines for their judicious and systematic use.

Heavy episodic drinking and alcohol consumption in French colleges: the role of perceived social norms.

BACKGROUND: The effect of normative perceptions (social norms) on heavy episodic drinking (HED) behavior is well known in the U.S. college setting, but little work is available in other cultural contexts. The objective of this study is therefore to assess whether social norms of alcohol use are related to HED in France, taking account of other influential predictors. METHODS: A cross-sectional survey was carried out among 731 second-year university students in the Paris region to explore the role of 29 potential alcohol use risk factors. The probability of heavy episodic drinking and the frequency of HED among heavy episodic drinkers were modeled independently. Monthly alcohol consumption was also assessed. RESULTS: Of the students, 56% overestimate peer student prevalence of HED (37% for alcohol drinking prevalence). HED frequency rises with perceived peer student prevalence of HED. Other social norms associated with HED are perceived friends' approval of HED (increasing both HED probability and HED frequency) and perceived friend prevalence of alcohol drinking (increasing HED probability only). Cannabis and tobacco use, academic discipline, gender, and the number of friends are also identified as being associated with HED. CONCLUSIONS: Overestimation of peer student prevalence is not uncommon among French university students. Furthermore, perceived peer student prevalence of HED is linked to HED frequency, even after adjusting for other correlates. Interventions correcting misperceived prevalences of HED among peer students have therefore the potential to reduce the frequency of HED in this population.

Budget impact model of rituximab after failure of one or more TNFalpha inhibitor therapies in the treatment of rheumatoid arthritis.

OBJECTIVES: To estimate the budget impact implied by the introduction of rituximab after failure of one or more anti-TNFalpha therapies in the perspective of the French health care system. METHODS: A Markov model reproduced the course, over 4years, of patients treated either by infliximab, etanercept, adalimumab or RTX, after failure of one or more anti-TNFalpha therapies, in a multicentric study. A sensitivity analysis was developed to account for patients in 3rd and subsequent lines of treatment who are expected to consume more healthcare resources. RESULTS: When RTX is not used, total annual medical cost is euro16,555 per patient, euro13,206 of which are dedicated to drug acquisition. When RTX is the only treatment in use, these costs decrease respectively to euro11,444 and euro7469. Total savings per patient and per year is euro5000. Over 4 years, total savings for the targeted population reach euro118M. In the sensitivity analysis, the difference between H2 and H2-coeff 2 (20%) reaches euro5,400,000 in total direct costs during the first year of simulation. This difference decreases along the period, to reach euro2,400,000 the fourth year of simulation, and is due to the fact that rituximab acquisition costs are independent from the treatment line. CONCLUSION: If TNFalpha inhibitors were the only treatment available, the annual global cost of treatment would be euro16,555 per patient versus euro11,444 for patients treated exclusively with rituximab. RTX is expected to produce important savings (-31%) if used after failure of one or more TNFalpha therapies. This is mainly due to its lower drug acquisition cost. These savings could increase with the development of rituximab in earlier stages of treatment.

Cost-effectiveness of activated protein C in real-life clinical practice.

BACKGROUND: Recombinant human activated protein C (rhAPC) has been reported to be cost-effective in severely ill septic patients in studies using data from a pivotal randomized trial. We evaluated the cost-effectiveness of rhAPC in patients with severe sepsis and multiple organ failure in real-life intensive care practice. METHODS: We conducted a prospective observational study involving adult patients recruited before and after licensure of rhAPC in France. Inclusion criteria were applied according to the label approved in Europe. The expected recruitment bias was controlled by building a sample of patients matched for propensity score. Complete hospitalization costs were quantified using a regression equation involving intensive care units variables. rhAPC acquisition costs were added, assuming that all costs associated with rhAPC were already included in the equation. Cost comparisons were conducted using the nonparametric bootstrap method. Cost-effectiveness quadrants and acceptability curves were used to assess uncertainty of the cost-effectiveness ratio. RESULTS: In the initial cohort (n = 1096), post-license patients were younger, had less co-morbid conditions and had failure of more organs than did pre-license patients (for all: P < 0.0001). In the matched sample (n = 840) the mean age was 62.4 +/- 14.9 years, Simplified Acute Physiology Score II was 56.7 +/- 18.5, and the number of organ failures was 3.20 +/- 0.83. When rhAPC was used, 28-day mortality tended to be reduced (34.1% post-license versus 37.4% pre-license, P = 0.34), bleeding events were more frequent (21.7% versus 13.6%, P = 0.002) and hospital costs were higher (47,870 euros versus 36,717 euros, P < 0.05). The incremental cost-effectiveness ratios gained were as follows: 20,278 euros per life-year gained and 33,797 euros per quality-adjusted life-year gained. There was a 74.5% probability that rhAPC would be cost-effective if there were willingness to pay 50,000 euros per life-year gained. The probability was 64.3% if there were willingness to pay 50,000 euros per quality-adjusted life-year gained. CONCLUSION: This study, conducted in matched patient populations, demonstrated that in real-life clinical practice the probability that rhAPC will be cost-effective if one is willing to pay 50,000 euros per life-year gained is 74.5%.