International longitudinal registry of patients with atrial fibrillation and treated with rivaroxaban: RIVaroxaban Evaluation in Real life setting (RIVER)

Atrial fibrillation (AF) is the most common sustained arrhythmia reported in adult patients [1] and is associated with an at least a five-fold increase in the risk of stroke [2]. Vitamin K antagonists (VKAs) formed the cornerstone of thromboembolic prophylaxis in patients with AF for many years. The introduction of non-vitamin K anticoagulants (NOACs), dabigatran, rivaroxaban, apixaban and edoxaban, provided physicians with agents with comparative efficacy and reduced potential for bleeding compared with vitamin K antagonists, while removing the need for dose titration, periodic laboratory testing and dietary restrictions that are necessary with VKAs [3‐5]. Evidence from phase III studies showed that rivaroxaban, one of several oral direct Factor Xa inhibitors, is noninferior to warfarin for the reduction of stroke or systemic embolism in patients with AF [6] and significantly reduces rates of intracranial and fatal haemorrhages, but not rates of bleeding overall. Based on these results, rivaroxaban is now licensed in more than 130 countries worldwide for stroke prevention in patients with AF.

Real-world studies (such as Global Anticoagulant Registry in the FIELD-AF [GARFIELD-AF] [7], ORBIT-AF I & II) [8] and GLORIA-AF [9, 10] have demonstrated that NOAC use is increasing while post-marketing surveillance (such as Xarelto® for Prevention of Stroke in Patients with Atrial Fibrillation [XANTUS]) [11] and national studies (such as the EXPAND) [12, 13] have provided data on the safety and efficacy of rivaroxaban. However, most of these registries are disease-specific and evaluate treatment patterns and outcomes across different treatments. Therefore, additional drug-specific observational studies are needed to assess the clinical and health economic risk-benefits of specific NOACs and in particular, the factors that could potentially influence outcomes (e.g. compliance with prescribing guidelines, persistence and comorbidities) for each treatment alternative separately. This paper describes the design of the RIVaroxaban Evaluation in Real life setting (RIVER) registry and baseline characteristics of patients who received rivaroxaban as part of routine care. This paper also includes an initial analysis of the doses of rivaroxaban used in everyday practice as well as a description of the use of rivaroxaban in combination with antiplatelets in different clinical scenarios, such as patients with renal impairment.

Observational or non-interventional studies play an important role in understanding and confirming the clinical effectiveness of interventions across the spectrum patients treated in routine practice.

RIVER is an independent treatment registry of patients from multiple care settings and patients were recruited from 17 countries. The RIVER registry provides an opportunity to examine the impact of different recruitment methodologies on the characteristics and treatment between the registries. RIVER will document the regional heterogeneity in the clinical presentation and assess the rate of stroke and systemic embolism and other outcomes with specific reference to the incidences of bleeding and therapy persistence. In addition to reporting on pre-specified clinical and economic outcomes, analyses from RIVER will be hypothesis generating, allowing the exploration of some aspects of the real world situation of AF treated with rivaroxaban and outcomes.

The degree of the patient involvement in the generation of data is expected to provide unique insights into the patients-reported outcomes. Patients’ experiences using antithrombotic treatment are recorded on the Anti-Clot Treatment Scale (ACTS) questionnaire. It is important to recognise that registries differ in their design, recruitment strategies, care settings, geographical spread and duration of follow-up. Compared to other ongoing prospective registries, the RIVER registry has the potential to capture the medicosocial burden due to AF in large-scale populations by employing broad inclusion and exclusion criteria in widely representative populations of patients with AF who are treated with rivaroxaban, across a range of clinical settings and to capture long-term follow-up data. The value of RIVER registry is enhanced by a quality assurance programme and the supervision of an independent Audit Committee, which oversees site-dependent verification, remote site monitoring and electronic database monitoring to ensure data quality.

There are several phase IV studies (such as XANTUS [15], XAPASS [16], XASSURE (China; NCT02784717) and registries such as EXPAND [12]) are ongoing to investigate rivaroxaban in patients with NVAF in the real world clinical settings. The XANTUS program comprises three studies: the XANTUS (Europe, Israel plus enrollment in Canada; NCT01606995), XANTUS-EL (Eastern Europe, Eastern Mediterranean, Middle East, Latin America; NCT01800006) and XANAP (Asia-Pacific; NCT01750788) [15].

Other ongoing non-interventional registries also provide real-world data on the effectiveness and safety of rivaroxaban, including the Global Anticoagulant Registry in the FIELD (GARFIELD)-AF [17], Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT)-AF I and ORBIT-AF II [18‐21], the Global Registry on Long-Term Oral Anthithrombotic Treatment in pateints with Atrial Fribrillation (GLORIA-AF) [22‐26] and the Dresden NOAC Registry [4, 5, 27] (Additional file 1: Table S2).

In the presence of all these observational studies, it is important to highlight that there are a number of important differences in the design (Additional file 1: Table S2) and recruitment of patients (Table 4) in RIVER compared with these registries. RIVER is a drug-specific registry which allows studying of drug utilisation patterns including off-label use whereas other registries like GARFIELD-AF, ORBIT-AF I and II, GLORIA-AF and Dresden NOAC are disease-specific registries which allows studying of burden, management and adverse event profile for different treatments related to a specific disease. Patients in XANTUS study were enrolled from Europe, Israel and Canada whereas EXPAND and XAPASS are Japanese registries and ORBIT-AF registries are restricted to USA [19]. By contrast, RIVER has recruited patients more broadly from 17 countries (outside Asia) including Europe, the Middle East, Latin America, Canada and Australia. RIVER provides long-term follow-up data of 2 years where as XANTUS had 1-year follow-up data. RIVER is a more contemporary population in which physicians’ now have experience using the NOACs. It is a known phenomenon that, after approval of new treatments, physicians start to apply these first in well-defined, carefully selected populations and expand it to other populations only after a period of time, which is reflecting learning curves based on increased comfort levels, communication of real world evidence, newly reported and previously unknown side effects or changes in guideline recommendations [28‐30] . As a consequence, treatment patterns and outcomes may shift over time, which is an additional justification for more contemporary registries in SPAF. All of these factors may have contributed to the observed differences in patients characteristics, compared to other observational studies. Patients in RIVER are younger (mean age: 69.5 years) than patients in EXPAND (72 yrs), XANTUS (71.5 yrs), and XAPASS (73.1 yrs). The mean BMI of patients in RIVER (29.2 ± 5.7) is higher than the Japanese cohort in XAPASS (23.7 ± 3.8) (Table 4). Patients studied in RIVER also had a lower risk of stroke, with a mean CHADS₂ scores of 1.9 and 13.4% had a prior episode of stroke/TIA/SE when compared to XANTUS (2.0, 19%) and XAPASS (2.2; 23.7%) (Additional file 1: Table S3) and other NOAC trials, such as RE-LY (2.1; 20.0%) and ARISTOTLE (2.1; 19.4%) [31, 32]. Nevertheless, patients in RIVER had high rates of comorbid conditions, including hypertension, hypercholesterolemia, diabetes mellitus, heart failure and coronary artery disease. However, the proportion of patients (8.6%) with renal dysfunction (CrCl < 50 mL/min) in RIVER was similar to XANTUS (9.4%) and lower than Japanese cohorts in EXPAND (20.8%) and XAPASS (23.9%); although this observation may be due to the higher rates of missing CrCl measurements in both RIVER (38.0%) and XANTUS (34.4%). Patients in RIVER and XANTUS received higher doses of rivaroxaban (20 mg/day [76.5 and 78.7% patients, respectively], 15 mg/day [20.0 and 20.8% patients, respectively]) than those in EXPAND (15 mg/day [56.6% patients], 10 mg/day [43.4% patients]), suggesting differences in the guideline recommendations, which are based on patient characteristics and ethnicities. In Japan, the regular dosage of rivaroxaban is 15 mg od, which is lower than the global recommended dosage of 20 mg od [33].

Centres for recruitment of patients in RIVER are limited to the care settings where rivaroxaban is the standard of care and includes sites beyond those included in the clinical trials. Comparison of different treatments are not possible, as there is no comparator drug, while larger prospective disease registries such as GARFIELD-AF and drug registries such as GLORIA-AF and ORBIT-II have the potential to conduct comparative effectiveness studies between different treatment approaches in newly diagnosed patients with AF. Due to the observational design of the study, laboratory and other investigations could not mandated.

RIVER is an independent academic research initiative. This prospective registry was designed with a novel approach to outcomes research, including the following features: sites representation of national AF care settings, randomised site selection, unselected eligible patients enrolled consecutively with a follow-up period of minimum 2 years and extensive monitoring and audit including source data verification of 10% of all eCRFs. Like other prospective registries, such as GARFIELD-AF [34], RIVER aims to overcome the inherent bias of retrospective cohort studies from national registries and claims databases [35‐39].

The RIVER prospective registry will expand our knowledge of how rivaroxaban is prescribed in everyday practice and whether evidence from clinical trials can be translated to the broader cross-section of patients treated in the real world.