{'fraction_non_alphanumeric': 0.03356064669373994, 'fraction_numerical': 0.024289326488391695, 'mean_word_length': 5.045391384900417, 'pattern_counts': {'":': 0, '<': 10, '<?xml version=': 0, '>': 3, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 3, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Rivaroxaban in acute venous thromboembolism: UK prescribing experience

Abstract Background Rivaroxaban was reported as effective as traditional therapies for the acute treatment of venous thromboembolism (VTE) with fewer major bleeding complications in the seminal Einstein program and is now a recommended option for the treatment of VTE around the world. Objective To report the safety and efficacy of rivaroxaban in daily care for the management of acute VTE in the United Kingdom. Patients/Method The FIRST registry is a UK‐only, multicenter, noninterventional, observational VTE study (NCT 02248610). Consecutive patients diagnosed with acute VTE, managed with rivaroxaban, were recruited and followed for up to 5 years. The primary outcomes were treatment‐emergent symptomatic objectively diagnosed recurrent VTE, major and clinically relevant nonmajor bleeding (CRNMB), and all‐cause mortality. Results A total of 1262 participants were recruited between 2014 and 2018. Participants were heterogeneous, with age range 18 to 95 years, weight 35 to 234 kg, and maximum body mass index 64.4 kg/m2. The median duration of treatment exposure was 135 days (interquartile range [IQR], 84‐307) and overall follow‐up 497 days (IQR, 175‐991). There were seven episodes of symptomatic VTE recurrence, 0.6%, (0.74/100 patient‐years; 95% confidence interval [CI], 0.19‐1.28). There were 79 of 1239 (6.4%), 8.66 of 100 patient‐years (95% CI, 6.90‐10.73) first episodes of major or CRNMB, which were most frequently reported by women aged <50 years as abnormal vaginal bleeding. Conclusions Rivaroxaban is an effective and safe single drug modality for the treatment of VTE in daily practice in the United Kingdom. Data to determine the optimal anticoagulation therapy for women of childbearing age are needed.


Essentials
• Safety and efficacy data for rivaroxaban for acute venous thromboembolism in daily practice in the United Kingdom are lacking.
• Our study demonstrates that rivaroxaban is highly effective in a low-risk population.
• The most frequent significant bleeding was abnormal vaginal bleeding in women aged <50 years.
• Data to determine the optimal anticoagulation therapy for women of childbearing age are needed. giving rise to concerns around adherence, especially in the first 30 days of treatment when the risk of VTE recurrence is between 0.6% and 5%. 6 A number of postmarketing observational studies have reported real-world experience of rivaroxaban for the treatment of VTE. [7][8][9][10][11] To date, postmarketing studies have corroborated the efficacy of rivaroxaban for the treatment of acute VTE from the phase III clinical trials, but safety findings are mixed despite the availability of standardized bleeding criteria. 12 Prospective data from clinical practice has reported the proportion of participants having bleeding events as 1.0% to 3.8%, 4.3% to 17.7%, and 9.1% to 45.5%, for major bleeding, clinically relevant nonmajor bleeding (CRNMB), or any bleeding, respectively. [7][8][9][10][11] Further data to understand the true incidence and the determinants of bleeding associated with rivaroxaban are needed.

| INTRODUC TI ON
In the United Kingdom, the management of VTE varies and takes place across a number of clinical settings. Patients with VTE can be managed in primary, secondary, or tertiary care, and are cared for by specialist nurses and pharmacists, as well as physicians. In the hospital setting, the clinical team responsible for patients with VTE could be the emergency department, cardiology, general medicine, or hematology. Further, the number or frequency of follow-up appointments is not mandated and varies across the United Kingdom.
The Follow-up in Rivaroxaban Patients in Setting of Thromboembolism (FIRST) registry opened to recruitment soon after the approval of rivaroxaban. The aim of the FIRST registry was to report on the safety and efficacy of rivaroxaban for the treatment of VTE across the United Kingdom in an unselected population and to describe treatment patterns in daily care.

| Study design and participants
The FIRST registry is a UK-only prospective, noninterventional, investigator-led, multicenter, observational cohort study (NCT02248610).
Patients were eligible for the study if they were aged >18 years, had a symptomatic objective diagnosis of DVT and/or PE confirmed by compression ultrasonography, contrast venography, computed tomographic (CT) venography or magnetic resonance venography for DVT, and ventilation/perfusion scan or CT pulmonary angiography for PE and were to be anticoagulated with rivaroxaban. Patients were recruited from routine clinical practice. This included VTE diagnosed during an unrelated in-patient stay, participants who were hospitalized for part or all of their DVT and/or PE treatment, or those managed exclusively in outpatient clinics or in primary care.
Interim heparin therapy for a maximum of 48 hours and/or a single dose of warfarin until definitive diagnostic testing had been completed was permitted. Patients needed to provide written informed consent. Once informed consent had been obtained, participants were followed for up to 5 years.
Patients were excluded if follow-up was unlikely or impossible, they were unable to give consent, they had received more than 48 hours of interim heparin therapy before an objective VTE diagnosis, had received more than one dose of warfarin, had an indication for anticoagulation other than VTE (eg, atrial fibrillation), or had any contraindication listed in the summary of product characteristics for rivaroxaban. 13 The study was open to recruitment between November 2014 and November 2018 and ceased follow-up July 2020.

| Selection of study sites
The FIRST registry was adopted by the National Institute of

| Data collection
Patient data were collected during the initial visit and routine follow-up visits, or by telephone contact, by the team directly responsible for patient care. The investigator collected relevant demographics, clinical characteristics, and medical history from medical records if available, or by interviewing the participant.
There were no specified follow-up visits, and follow-up occurred according to routine clinical practice at each local site, anticipated at 3 months, 6 months, and annually thereafter for those on longterm treatment.
Participants with both distal and proximal DVTs as index events were included, and those with involvement of the popliteal vein were categorized as proximal for the purpose of this study. The severity of PE was calculated using both the simplified Pulmonary Embolism Severity Index (sPESI) and the Pulmonary Embolism Severity Index (PESI) score. 14,15 Creatinine clearance (CrCl) was calculated using the Cockcroft Gault equation, 16 and participants were defined as fragile if they were either aged >75 years, <50 kg, or had CrCl < 50 mL/min, as has previously been reported by the EINSTEIN investigators. 3 The FIRST registry used Progeny Clinical for the electronic case report form. Data were entered locally, and the lead investigating site reviewed the completeness and accuracy of the data collected.
A 100% source data verification took place for DVT diagnosis for sites recruiting >15 participants, and all suspected episodes of recurrent VTE were subject to central adjudication. The data were extracted from the study database on August 20, 2020.

| Outcomes
The primary efficacy outcome was incidence of recurrent VTE.
Recurrent VTE was defined as a symptomatic event objectively confirmed by compression ultrasonography, contrast venography, CT venography, or magnetic resonance venography for DVT, and ventilation/perfusion scan, or CT pulmonary angiography for PE.
Major bleeding (MB) and CRNMB were the primary safety outcomes. The site of bleeding was reported as well as the bleed severity as defined by the ISTH. 12,17 Secondary safety outcomes included all-cause mortality and the rates of nonhemorrhagic stroke/transient ischemic attack and myocardial infarction.

| Sample size
The target sample size was based on the combined analysis of the EINSTEIN DVT and PE studies that reported the rate of major bleeding and VTE recurrence as 1% and 2.1%, respectively. 3 For the recurrent VTE incident rates, assuming an incidence rate of ≈2.1%, 1500 patients would provide an estimate of this value with 95% CI ± 0.7%.
For major bleeding assuming the major bleeding is ≈1%, 1500 patients were required in order to provide an estimate of this value with 95% CI ± 0.5%.
The sample size was reduced by the sponsor to 1250 in light of recruitment challenges in the early stages of the study. A total of 1250 patients would provide an estimate of recurrent VTE incident rates with 95% CI ± 0.8% and for major bleeding of 95% CI ± 0.6%.

| Statistical analysis
The data were divided into two clearly defined data sets for analy- Recurrent VTE and MB/CRNMB rates are reported as a crude incidence and as incidence rates, presented as event per 100 patientyears, with corresponding confidence intervals (CIs). Outcomes were compared between subgroups using the chi-squared/Fisher's exact test or t test as appropriate.
To show the differences between groups for time to the bleeding event, Kaplan-Meier plots were developed, and comparisons made between groups using the log-rank test. A Cox proportional hazards model was also performed to investigate factors associated with the safety outcome. Significance was set at P < .05.

| Clinical outcomes
There were seven episodes of VTE recurrence while participants were prescribed rivaroxaban (0.6%, 0.74/100 patient-years; 95% CI, 0.19-1.28; Table 3). Five were associated with nonadherence, and two were considered treatment failures. The treatment failures were objectively diagnosed, symptomatic events following   Figure 2 shows the time to event analysis for CRNMB or MB stratified by age ( Figure 2A) and age and sex ( Figure 2B) up to 1 year. Figure 2A illustrates that the risk of CRNMB or MB is higher for participants aged <50 years compared with ≥50 years, and Figure 2B illustrates that this is predominantly seen in women aged <50 years.  Figure S1A reports the time to CRNMB or MB in participants aged <50 years. Younger female participants experienced significantly more bleeding complications than did male patients of the same age (P < .001). Between the ages of 50 and 60 years, no sex difference was observed ( Figure S1B), and then over 60 years, more male participants report CRNMB or MB, although not statistically significantly ( Figure S1C). Over age F I G U R E 2 Kaplan-Meier curve for clinically relevant major or nonmajor bleeding stratified by age <50/≥50 and sex (A) stratified by age alone and (B) stratified by age and sex. CRNMB, clinically relevant nonmajor bleeding; MB, major bleeding 70 years, more women appeared to experience more bleeding, although this did not reach statistical significance ( Figure S1D).

| DISCUSS ION
We report the results of a large multicenter registry for patients prescribed rivaroxaban for the treatment of acute VTE in routine clinical practice. Routine clinical practice was heterogeneous; rivaroxaban was prescribed by emergency departments, thrombosis teams, and cardiologists as well as general practitioners in primary care.
The 1262 participants exemplify an unselected real-world population with bodyweight ranging from 35 to 234 kg, age range 18 to 95 years, and a creatinine clearance ranging from 21 to 367 mL/min, the majority of whom were managed with the same fixed dose of rivaroxaban.
The FIRST registry demonstrates that rivaroxaban is a safe and effective, single-modality treatment for acute VTE that most patients tolerate well; with a low rate of VTE recurrence and major bleeding. VTE recurrence and major bleeding rates were comparable with EINSTEIN and Xarelto for Long-Term and Initial Anticoagulation in Venous Thromboembolism (XALIA) ( Table 6). 3,20 Rates of VTE recurrence and bleeding reported from real-world data is varied.
Differences are most likely due to the variation in study methodologies, such as data capture and the frequency of study follow-up.
The FIRST registry results were comparable with those of the Home Treatment of Pulmonary Embolism (HOT-PE) study, which reported safety and efficacy data for rivaroxaban for low-risk PE (VTE recurrence 0.6% and 0.6%, respectively). 21  There are a number of limitations that should be considered.
While the FIRST registry endeavored to capture rivaroxaban prescribing in routine practice, there were some patients from important vulnerable subgroups that were not recruited ( Figure 1). This phenomenon has been reported in the setting of phase III clinical trials, which describe the selected populations that often participate in clinical research. 34,35 Second, given the registry design, there is a risk of underreporting of primary outcomes and missing data.
There also may have been selection bias, since treatment was determined by the patient and care provider rather than the registry