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. 1 INTRODUCTION

For decades, the standard treatment for acute venous thromboembolism (VTE) has been vitamin K antagonists (VKAs), typically warfarin in the United Kingdom. In 2012, there was a significant shift in the treatment of acute VTE with the licensing of rivaroxaban, the first direct oral anticoagulant (DOAC) to become available for the treatment of VTE.1, 2 This promised a much welcomed simpler approach to anticoagulation in comparison to traditional therapies—with a fixed dose, no requirement for bridging therapy and no international normalized ratio (INR) monitoring. In the seminal phase III randomized control trials, rivaroxaban was found to have similar efficacy to traditional therapy, with a lower rate of major bleeding for both deep vein thrombosis (DVT) and pulmonary embolism (PE) indications.3 However, in the absence of the close monitoring of a clinical trial, there were concerns about how fixed-dose rivaroxaban might perform in daily care in an unselected population and what the long-term outcomes might be.4, 5 Furthermore, the intensive follow-up of the DOAC phase III clinical trials is not typically replicated in routine care, 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.7-11 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.7-11 Further data to understand the true incidence and the determinants of bleeding associated with rivaroxaban are needed.

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.

2 METHODS 2.1 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.

2.2 Selection of study sites

The FIRST registry was adopted by the National Institute of Health Research (NIHR) clinical research network (CRN) portfolio in the United Kingdom (UK CRN ref: 17766). Using the NIHR CRN, centers expressed interest in participating to the lead site and sponsor, King’s College Hospital, London. Local sites were selected to participate if rivaroxaban was the local treatment of choice for acute VTE. The recruiting centers are listed in the Supporting Information and included a mix of secondary and tertiary care providers.

2.3 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 long-term 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.

2.4 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.

2.5 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%.

2.6 Statistical analysis

The data were divided into two clearly defined data sets for analysis. Efficacy outcomes were reported from the intention-to-treat (ITT) population. The ITT population was defined as any patient who had consented to the study regardless of the duration of rivaroxaban received or if there were a change of treatment regimen. Safety outcomes were reported from the safety population, defined as participants who were recruited to the study who had received ≥1 day of rivaroxaban therapy and included those who temporarily interrupted or permanently discontinued treatment, or switched to an alternative anticoagulant. Bleeding events were reported for participants on rivaroxaban therapy and for up to 48 hours after the last dose. Baseline characteristics are reported as absolute and relative frequencies, mean and standard deviation, or median with interquartile ranges where appropriate. Participants with missing data were not removed from the analysis, and an available case analysis was conducted. All statistical analysis was performed using SPSS Statistics for Windows version 25.0 (IBM, Armonk, NY, USA).

Recurrent VTE and MB/CRNMB rates are reported as a crude incidence and as incidence rates, presented as event per 100 patient-years, 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.

2.7 Ethics statement

Ethical approval was obtained from the West of Scotland Research Ethics Service (14/WS/1120). Each participating National Health Service (NHS) Trust participating in the study also obtained local research and development approval before opening. The study complied with the principles and requirements of the Declaration of Helsinki. All participants provided written informed consent to participate; confidentiality and anonymity were maintained.

3 RESULTS

Between December 2014 and November 2018, 1262 patients were recruited to the FIRST registry from 22 NHS trusts. A Consolidated Standards of Reporting Trials diagram is presented in Figure 1.

Consolidated Standards of Reporting Trials diagram for the FIRST Registry. Screening/eligibility data was gathered by 16 of 22 sites recruiting to FIRST (The six sites that did not contribute this data had 164 participants in total [13%], median 19.5 participants per site recruited [IQR, 6-40]). * See Supporting Information

Patient characteristics stratified by index event and risk factors for VTE are described in Tables 1 and 2, respectively.

TABLE 1. Patient characteristics of those recruited to the FIRST registry

DVT

(N = 956)

PE

(N = 306)

Overall

(N = 1262)

Sex Female, n (%) 351 (36.7) 127 (41.5) 478 (37.9) Male, n (%) 604 (63.2) 178 (58.2) 782 (62.0) Transgender, n (%) 1 (0.1) 1 (0.3) 2 (0.2) Age Mean [SD] 58.6 [15.4] 58.8 [16.0] 58.7 [15.5] Race/Ethnicity White, n (%) 828 (88.7) 265 (88.0) 1093 (88.6) Black, n (%) 73 (7.8) 27 (9.0) 100 (8.1) Asian, n (%) 26 (2.8) 5 (1.7) 31 (2.5) Mixed, n (%) 6 (0.6) 4 (1.3) 10 (0.8) Unknown, n 23 5 28 Diagnosis Distal DVT, n (%) 371 (38.8) – 371 (29.4) Proximal DVT, n (%) 563 (58.9) – 563 (44.6) PE, n (%) – 277 (90.5) 277 (21.9) DVT and PE, n (%) – 29 (9.5) 29 (2.3) Upper limb, n (%) 22 (2.3) – 22 (1.7) Bodyweight (kg) Mean (SD) 87.7 (19.5) 87.8 (23.6) 87.7 (20.5) Bodyweight categorization (kg) ≤49 kg, n (%) 7 (0.7) 7 (2.3) 14 (1.1) 50–99 kg, n (%) 738 (77.8) 228 (76.3) 966 (77.4) 100–149 kg, n (%) 199 (21.0) 57 (19.1) 256 (20.5) ≥150 kg, n (%) 5 (0.5) 7 (2.3) 12 (1.0) Unknown, n 7 7 14 Creatinine clearance (mL/min)a Mean (SD) 106 (40.4) 106 (45.6) 106 (41.7) Creatinine clearance categorization (mL/min) ≤29 mL/min, n (%) 4 (0.4) 1 (0.3) 5 (0.4) 30–49 mL/min, n (%) 43 (4.7) 12 (4.1) 55 (4.5) 50–89 mL/min, n (%) 305 (33.1) 107 (36.9) 412 (34.0) ≥90 mL/min, n (%) 569 (61.8) 170 (58.6) 739 (61.0) Unknown, n (%) 35 16 51 BMI categorization (kg/m2) Underweight, n (%) <18.5 10 (1.1) 4 (1.4) 14 (1.2) Normal, n (%) 18.5–25 212 (22.9) 70 (24.3) 282 (23.3) Overweight, n (%) 25–30 337 (36.5) 102 (35.4) 439 (36.2) Obese (class I), n (%) 30–35 213 (23.1) 56 (19.4) 269 (22.2) Obese (class II), n (%) 35–40 102 (11.0) 35 (12.2) 137 (11.3) Obese (class III), n (%) >40 50 (5.4) 21 (7.3) 71 (5.9) Unknown, n 32 18 50 Treatment for suspected VTE before objective diagnosis No treatment received before objective diagnosis, n (%) 565 (59.3) 113 (37.4) 678 (54.0) LMWH (1 dose), n (%) 243 (25.5) 119 (39.4) 362 (28.8) LMWH (2 doses), n (%) 90 (9.4) 59 (19.5) 149 (11.9) Rivaroxaban, n (%) 53 (5.6) 9 (3.0) 62 (4.9) Unfractionated heparin, n (%) 1 (0.1) 1 (0.3) 2 (0.2) Warfarin, n (%) 1 (0.1) 1 (0.3) 2 (0.2) Unknown, n 3 4 7 Abbreviations: BMI, body mass index; DVT, deep vein thrombosis; FIRST, Follow-up in Rivaroxaban Patients in Setting of Thromboembolism; LMWH, low-molecular-weight heparin; PE, pulmonary embolism; SD, standard deviation; VTE, venous thromboembolism. a Creatinine clearance at baseline calculated using Cockcroft-Gault and total bodyweight. TABLE 2. VTE risk factors reported in the FIRST registry VTE risk factor

N = 1262

n (%)

Personal history of VTE No personal history of VTE 974 (77.5) One previous VTE event 241 (19.2) >1 previous VTE event 42 (3.3) Unknown 5 Family history of VTE No family history 1052 (84.1) Family history 199 (15.9) Unknown 11 Line-associated VTE Not applicable 1236 (98.6) Line related 18 (1.4) Unknown 8 Recent surgery No surgery within 12 weeks 1117 (88.9) <4 weeks 59 (4.7) 4-8 weeks 58 (4.6) 8-12 weeks 22 (1.8) Unknown 6 Recent medical illness requiring hospitalization No medical illness within 12 weeks 1199 (95.8) <4 weeks 34 (2.7) 4-8 weeks 17 (1.4) 8-12 weeks 2 (0.2) Unknown 10 Cancera No cancer 1216 (96.8) Active cancer 17 (1.4) Palliative care 1 (0.1) Cancer treated within 6 months 7 (0.6) Cancer diagnosed after index VTE within 6 months 10 (0.8) Cancer diagnosed after index VTE after 6 months 5 (0.4) Unknown 6 Pregnancy Not pregnant in the last 6 weeks 389 (98.7) Miscarriage (<6 weeks) 1 (0.3) Postpartum (<6 weeks) 4 (1.0) Unknown 84 Contraception No contraception 402 (87.0) Combined oral contraceptive 41 (8.9) Contraceptive patch 3 (0.6) Progesterone-only oral contraceptive 14 (3.0) Transdermal implant 2 (0.4) Unknown 16 HRT No HRT 465 (96.9) Oral HRT containing estrogen 10 (2.1) Transdermal estrogen 4 (0.8) Local estrogen application 1 (0.2) Immobilization (paralysis, paresis, or plaster cast) No immobilization 1165 (93.4) <4 weeks 56 (4.5) 4-8 weeks 16 (1.3) 8-12 weeks 10 (0.8) Unknown 15 Smoking Never 670 (54.0) Current 202 (16.3) Ex-smoker 368 (29.7) Unknown 22 IVDU Never 1205 (98.8) Current 2 (0.2) Ex-IVDU 13 (1.1) Unknown 42 Recent long-distance travelb No travel 1094 (86.7) Recent long-distance travel 168 (13.3) Known thrombophiliaa 22 (1.7) Provoking factorsc Unprovoked 971 (76.9) Cancer-associated thrombosisa 35 (2.8) Nonsurgical risk factor 147 (11.6) Surgical risk factor 109 (8.6) Abbreviations: FIRST, Follow-up in Rivaroxaban Patients in Setting of Thromboembolism; HRT, hormone replacement therapy; IVDU, intravenous drug user; VTE, venous thromboembolism. a Further detail in Supporting Information. b Long distance travel was defined for the purpose of this study as travel over 4 hours up to 8 weeks before the index event. Long-distance travel was not considered a provoking factor for this analysis. c Provoking factors were categorized according to the American College of Chest Physicians guidance.18 A major transient risk factor, VTE provoked by major surgery/major trauma within past 3 months; nonsurgical transient risk factor (eg, estrogen therapy, pregnancy, immobilization); cancer-associated VTE (defined as cancer diagnosed within the previous 6 months; recurrent, regionally advanced, or metastatic cancer; cancer for which treatment had been administered within the previous 6 months; or hematologic cancer that was not in complete remission).

The mean age of participants was 58.7 years (standard deviation ± 15.5) and 782 (62.0%) were men. The majority of patients had lower-limb DVTs (n = 934, 74.0%; distal, n = 371, 29.4%; and proximal, n = 563, 44.6%), and 277 (21.9%) had a PE only. Twenty-two patients (1.7%) had an upper-limb thrombosis.

The PESI and sPESI were completed by 191 of 306 and 220 of 306 index events of PE ± DVT, respectively. Participants were found to be low risk in 154 of 191 (80.6%) and 151 of 220 (68.6%) according to the PESI and sPESI, respectively. Over half of study participants received either no bridging therapy with low-molecular-weight heparin (LMWH) or were started on rivaroxaban pending a definitive diagnosis of VTE with rivaroxaban (n = 741, 58.7%). The total follow-up was 497 days (interquartile range [IQR], 175-991), and the median duration of exposure on rivaroxaban was 135 days (IQR, 84-307).

3.1 Treatment patterns

Rivaroxaban was prescribed according to the recommended dose of 15 mg twice daily at initiation in 98.8% of participants. It was prescribed for 3 weeks in the majority of patients, with 83.5% switching to the maintenance dose at 21 days ± 2 days. While the frequency of unlicensed initiation doses was low, doses ranged from 10 mg once daily to 25 mg twice daily. The standard maintenance dose of 20 mg once daily was prescribed in 97.2% of participants, with 21 participants (1.7%) receiving 15 mg once daily as the maintenance dose. Five participants switched to LMWH before the scheduled dose change, three due to investigations for malignancy, one stroke, and one rash.

Two hundred twenty patients (17.4%) were admitted to the hospital for management of their index VTE event; 122 (55.5%) of those participants had had a PE. The median stay was 2 days (IQR, 1-3 days).

Half of the participants in the safety population completed rivaroxaban as planned (625/1239, 50.4%) at a median 98 days (IQR, 85-175 days). Eight participants permanently discontinued anticoagulation therapy after experiencing an adverse effect on rivaroxaban, and 2 of 8 discontinued before completing 3 months of anticoagulation. In total, 121 of 1262 (9.6%) patients switched from rivaroxaban to an alternative agent; the reasons for switching are described later.

Long-term treatment with rivaroxaban was recommended in 324 of 1262 (25.7%) of cases. Thirty-five participants (2.8%) had a rivaroxaban dose reduction to 10 mg once daily for secondary VTE prevention.

Thirty participants (2.4%) did not have a treatment plan recorded, and 72 of 1262 (5.7%) had no follow up data reported.

3.2 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 uninterrupted rivaroxaban therapy. Both episodes resulted in participants changing to an alternative anticoagulant: LMWH/warfarin and apixaban. Of note, all episodes of recurrence occurred in men with lower-limb DVTs (six proximal and one distal). Five of the seven events were unprovoked. There were no episodes of recurrence in participants with cancer and one episode of recurrence in a participant weighing 135 kg (associated with nonadherence) as previously reported.19 There were 78 of 1262 episodes of VTE recurrence (6.2%) that occurred when the participants were no longer prescribed rivaroxaban.

TABLE 3. Efficacy and safety results Events on or off rivaroxaban Events while prescribed rivaroxaban Efficacy outcomes Intention to treat N = 1262 Recurrent VTE, n (%) 85 (6.7) 7 (0.6) Treatment failure, n (%) … 2 (0.2) Nonadherence, n (%) … 5 (0.4) Safety outcomes Safety population N = 1239 Bleeding Major bleeding, n (%) … 11 (0.9) Clinically relevant nonmajor bleeding, n (%) … 68 (5.5) Myocardial infarction, n (%) 8 (0.6) 6 (0.5) CVA or TIA, n (%) 6 (0.5) 3 (0.2) Death 37a (3.0) 7 (0.6) Cancer-related death, n (%) 13 (1.0) 2 (0.2) Not VTE or anticoagulation related death, n (%) 13 (1.0) 4 (0.3) Cause unknown, n (%) 11 (0.9) 1 (0.1) Abbreviations: CVA, cerebrovascular accident; TIA, transient ischemic attack; VTE, venous thromboembolism. a One patient was lost to follow up and therefore the cause of death and whether they were prescribed rivaroxaban at the time of death is unknown.

A first treatment-emergent bleeding event (all severities) was reported by 129 of 1239 (10.4%) of participants in the safety population. Overall, there were 157 episodes of bleeding reported, as some participants reported more than one episode (Table 4).