Rivaroxaban real-world evidence: Validating safety and effectiveness in clinical practice

Transcription

1 Thrombosis and Haemostasis Supplement S13 Rivaroxaban real-world evidence: Validating safety and effectiveness in clinical practice Jan Beyer-Westendorf 1 ; A. John Camm 2 ; Craig I. Coleman 3 ; CAPT Sally Tamayo 4 1 University Hospital Carl Gustav Carus Dresden, Germany; 2 St George s University of London and Imperial College, London, UK; 3 University of Connecticut School of Pharmacy, Storrs, Connecticut, USA; 4 Naval Medical Center Portsmouth, Portsmouth, Virginia, USA Summary Randomised controlled trials (RCTs) are considered the gold standard of clinical research as they use rigorous methodologies, detailed protocols, pre-specified statistical analyses and well-defined patient cohorts. However, RCTs do not take into account the complexity of real-world clinical decision-making. To tackle this, real-world data are being increasingly used to evaluate the long-term safety and effectiveness of a given therapy in routine clinical practice and in patients who may not be represented in RCTs, addressing key clinical questions that may remain. Real-world evidence plays a substantial role in supporting the use of non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) in clinical practice. By providing data on patient profiles and the use of anticoagulation therapies in routine clinical practice, realworld evidence expands the current awareness of NOACs, helping to ensure that clinicians are well-informed on their use to implement patient-tailored clinical decisions. There are various issues with current anticoagulation strategies, including under- or overtreatment and frequent monitoring with VKAs. Real-world studies have demonstrated that NOAC use is increasing (Dresden NOAC registry and Global Anticoagulant Registry in the FIELD-AF [GARFIELD-AF]), as well as reaffirming the safety and effectiveness of rivaroxaban previously observed in RCTs (XArelto on prevention of stroke and non-central nervous system systemic embolism in patients with non-valvular atrial fibrillation [XANTUS] and IMS Disease Analyzer). This article will describe the latest updates in real-world evidence across a variety of methodologies, such as non-interventional studies (NIS), registries and database analyses studies. It is anticipated that these studies will provide valuable clinical insights into the management of thromboembolism, and enhance the current knowledge on anticoagulant use and outcomes for patients. Correspondence to: Jan Beyer-Westendorf Center for Vascular Medicine University Hospital "Carl Gustav Carus" Technical University Dresden Fetscherstrasse 74, Dresden, Germany Tel.: jan.beyer@uniklinikum-dresden.de Financial support: Editorial support was funded by Bayer Pharma AG. Received: June 29, 2016 Accepted: July 10, 2016 Epub ahead of print: September 14, Thromb Haemost 2016; 116 (Suppl 2): S13 S23 Introduction Randomised controlled trials (RCTs) are regarded as the gold standard of clinical research since they use a rigorous methodology, detailed protocols and pre-specified statistical analyses. They evaluate the safety and efficacy of a therapy in a well-defined patient cohort selected according to strict inclusion and exclusion criteria (1, 2). These pre-defined features and patient profiles are very specific, and do not adequately reflect real-world scenarios or take into account the complexity of real-world clinical decisionmaking (2). Real-world data are now being used to help describe a therapy s actual clinical profile and effectiveness in the routine clinical setting, providing data on patients that may not be collected in RCTs (e. g. those with comorbidities, the elderly and younger patients), as well as long-term safety (3). Hence, the ideal scenario would include confirming RCT data in a more heterogeneous population with real-world clinical experiences. Real-world studies can contribute to a range of evidence areas ( Table 1) (4). Further information can be garnered on treatment adherence and persistence, current prescription activities and guideline adherence, and health and economic outcomes research (HEOR), which are now important in satisfying requests from payors and regulators (2, 4). A variety of real-world research methodologies, such as noninterventional studies (NIS), registries and database studies (2), provide informative and insightful clinical evaluations of oral anticoagulation, both with vitamin K antagonist (VKA) or non-vka oral anticoagulants (NOACs), namely apixaban, edoxaban, rivaroxaban and dabigatran. There is a wealth of RCT data on NOACs for the management of thromboembolism (5), and realworld data have added to this body of knowledge. The direct, oral factor Xa inhibitor rivaroxaban has a broad evidence base built from both RCT and real-world studies, and this article will describe the latest updates in real-world evidence relating to its use. Non-interventional studies Regulatory authorities and payors have recently started to request real-world data from Phase IV studies, in addition to Phase III

2 S14 Beyer-Westendorf et al. Update on rivaroxaban real-world evidence Table 1: Real-world evidence areas (4). Long-term effectiveness and safety data Validating safety and effectiveness in a heterogeneous population Adherence and persistence trends Treatment and disease patterns HEOR (Health economic outcomes research) analyses RCT programmes, in order to justify certain coverage and reimbursement decisions (2, 6). NIS explore various aspects of an agent, including effectiveness and safety, under real-world conditions (7). The patient is treated as per the physicians own treatment paradigms (7), which may not necessarily be in accordance with the manufacturers protocols. XANTUS: Real-world rivaroxaban use for the treatment of non-valvular AF XArelto on prevention of stroke and non-central nervous system systemic embolism in patients with non-valvular atrial fibrillation (XANTUS) is the first large, prospective, single-arm, observational Phase IV study of rivaroxaban for stroke prevention in non-valvular atrial fibrillation (AF) (8). XANTUS was conducted at 311 centres across Europe, Canada and Israel and was designed to determine whether the safety profile of rivaroxaban previously described in the Phase III RCT, Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF), is also observed in routine clinical practice (refer to Table 2 for further study information) (8, 9). Independently adjudicated primary outcomes included major bleeding (using International Society on Thrombosis and Haemostasis [ISTH] criteria), all-cause mortality, stroke and systemic embolus, any other adverse events (AEs) and serious AEs (8). Overall duration of follow-up for each patient was 1 year, with intermediate follow-up visits at approximately 3-month intervals (8). The XANTUS study forms part of a larger programme that includes Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation in Asia-Pacific (XANAP, Clinicaltrials.gov identifier: NCT ) (10), and Xarelto for Prevention of Stroke in Patients with Non-valvular Atrial Fibrillation, Eastern Europe, Middle East, Africa and Latin America (XANTUS-EL, Clinicaltrials.gov identifier: NCT ) (11). Across the wide range of patients with NVAF in XANTUS, comorbidities were common, and included hypertension (74.7 %), diabetes (19.6 %), prior stroke, systemic embolism (SE) or transient ischaemic attack (TIA; 19.0 %), and congestive heart failure (18.6 %) (9). When considering the risk profile of the XANTUS population, the mean CHADS 2 (Congestive heart failure, Hypertension, Age, Diabetes, and Prior Stroke/TIA) score was 2.0 and the mean CHA 2 DS 2 -VASc (Congestive heart failure, Hypertension, Age, Diabetes, and Prior Stroke/TIA, Vascular disease, Age, Sex category) score was 3.4 (9). A minority of patients in XANTUS (4.3 %, 267/6784) experienced any treatment-emergent major bleeding, stroke/se or death (9). Stroke occurred at a rate of 0.7 events per 100 patient-years and SE at a rate of 0.1 events per 100 patient-years. Rates of major bleeding events with rivaroxaban were low at 2.1 events per 100 patient-years (ranging from 0.9 events per 100 patient-years [patients aged <65 years] to 3.2 events per 100 patient-years [patients aged >75 years]); rates of fatal bleeding (0.2 events per 100 patientyears), critical organ bleeding (0.7 events per 100 patient-years, including intracranial haemorrhage [ICH] at 0.4 events per 100 patient-years) and major gastrointestinal (GI) bleeding (0.9 events per 100 patient-years) were correspondingly low ( Figure 1) (9). Patients with higher CHADS 2 or CHA 2 DS 2 -VASc scores in XANTUS had higher rates of stroke/se, as well as a higher risk of major bleeding and all-cause death. In terms of renal function, the highest rates of major bleeding were seen in those with creatinine clearance [CrCl] <50 ml/minute [min] (3.4 % overall) (9). Major bleeding was mostly treated using conservative methods (such as transfusion of 2 units of packed red blood cells or whole blood); universal reversal agents, such as prothrombin complex concentrate (PCC), were rarely used. All-cause mortality occurred at a rate of 1.9 events per 100 patient-years (N=118 patients), with cardiovascular (CV) causes (41.5 %; 20.3 % of these being due to heart Table 2: Real-world evidence studies overview. Study name Design Objective Timeline Non-interventional XANTUS (XArelto on prevention of stroke and non-central nervous system systemic embolism in patients with NVAF) (8) International, prospective, single-arm, non-interventional Phase IV study; n=6785 enrolled To investigate the safety and effectiveness of rivaroxaban in routine clinical use in the NVAF setting June 2012 Dec 2013 XALIA (XA inhibition with rivaroxaban for Long-term and Initial Anticoagulation in venous thromboembolism) (18) International, prospective, non-interventional study; n=5142 enrolled To evaluate the safety and effectiveness of rivaroxaban for the treatment of symptom atic DVT in patients typically seen and managed in routine practice, and to meet a regulatory request during the assessment procedure for marketing authorisation from the EMA June 2012 Mar 2014 Thrombosis and Haemostasis Supplement 2/2016 Schattauer 2016

3 Beyer-Westendorf et al. Update on rivaroxaban real-world evidence S15 Table 2: Continued. Study name Registries GARFIELD-AF (Global Anticoagulant Registry in the FIELD-AF) (24, 64, 65) GARFIELD-VTE (Global Anticoagulant Registry in the FIELD-VTE) (33) ORBIT-AF I (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) (66, 67) ORBIT-AF II (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II) (68) Dresden NOAC registry (69) Databases US Department of Defense Military Health System US Truven Health MarketScan IMS Disease Analyzer Design International, prospective, observational, multicentre; n=57,000 (target) International, prospective, observational, multicentre; n=10,000 (target) USA; prospective, multicentre, outpatient registry; n=10,179 enrolled USA; prospective, multicentre, outpatient registry; n=15,000 (target) Germany; prospective, observational database of private practices and community hospitals; n=>2000 (target) USA; retrospective, observational claims database; ~10 million EMRs (exclusively military service members and their families) US; retrospective Commercial Claims and Medicare Supplemental database; >30 million residents Germany; retrospective longitudinal database; 15.5 million EMRs Objective To evaluate the management and outcomes of patients with newly diagnosed NVAF and at least one additional risk factor for stroke To evaluate acute and long-term management and outcomes in patients with symptomatic DVT or PE treated in a real-world setting with both traditional standard of care and NOACs To characterise and describe a large representative population of patients with AF, including current practice patterns and subsequent outcomes; adherence and resource use associated with current anticoagulant prophylaxis strategies; the adoption and impact of emerging antithrombotic/anti-arrhythmic therapies on outcomes in AF, including PROs and healthcare resource use To evaluate the safety and clinical outcomes with NOACs in outpatients with AF, and describe their characteristics and management To characterise the patient profiles of those receiving NOACs, as well as treatment patterns and long-term effectiveness and safety of NOACs in a number of settings Has been used to gain further knowledge and insight regarding major bleeding with rivaroxaban in the postapproval setting, via the PMSS (14) To be used as a tool to evaluate realworld occurrence of ischaemic stroke and intracranial haemorrhage in patients with NVAF taking either rivaroxaban or warfarin (55) To describe real-world practices with rivaroxaban in patients with NVAF, including clinical effectiveness, safety, persistence and adherence (49, 50) Timeline Dec 2009 July 2018 Mar 2014 Dec 2018 June 2010 Dec 2014 Feb 2013 Feb 2018 Sept 2011 ongoing Jan 2013 Jan 2018 Jan 2012 Oct 2014 Jan 2012 October 2013 (50) and Jan 2012 August 2013 (49) EMRs from the US Department of Defense (DoD) Military Health System (MHS). AF: Atrial fibrillation; DVT: Deep-vein thrombosis; EMA: European Medicines Agency; EMRs: Electronic medical records; NOAC; Non-vitamin K antagonist oral anticoagulant; PE: Pulmonary embolism; PMSS: Post-Marketing Surveillance Study; PROs: Patient-reported outcomes; USA: United States of America; VTE: Venous thromboembolism. failure) being the most frequent followed by cancer (19.5 %) (9, 12). Although the results of XANTUS cannot be directly compared to those from ROCKET AF, it is worth noting that the incidence of major bleeding in XANTUS (2.1 events per 100 patient-years) was consistent with that observed for patients with NVAF receiving rivaroxaban in ROCKET AF (3.6 events per 100 patient-years) and rates of ICH, critical organ bleeding and fatal bleeding were similarly low (9, 13). Importantly, major GI bleeding incidence rates observed in XANTUS (0.9 events per 100 patient-years) were lower

4 S16 Beyer-Westendorf et al. Update on rivaroxaban real-world evidence than rates in ROCKET AF (2.0 events per 100 patient-years) (9, 12, 13). Furthermore, the incidence of major bleeding in XANTUS was either similar to or lower than that observed in other real-world studies covered later in this article ( Figure 2) (9, 13 15). A subgroup analysis using XANTUS data compared baseline characteristics and outcomes in patients dosed in accordance with the recommended label (20 mg once daily [Q. D.], or 15 mg Q. D. for patients with CrCl ml/min) with those in whom Figure 1: Primary efficacy (A) and safety (B) outcomes observed with rivaroxaban in the XANTUS study (9). Events per 100 patientyears. CHADS 2 : Congestive heart failure, Hypertension, Age >75, Diabetes mellitus; and prior Stroke or transient ischaemic attack; ICH: Intracranial haemorrhage; GI: Gastrointestinal. Figure 2: Rivaroxaban-associated bleeding outcomes across real-world studies (9, 13 15). Events per 100 patient-years. Major bleeding defined using International Society on Thrombosis and Haemostasis [ISTH] criteria; Major bleeding was defined using the Cunningham algorithm that closely approximates the ISTH major bleeding definition; ǁ The mean CHADS 2 scores depicted for ROCKET AF, Dresden NOAC registry and XANTUS cover the overall population; the mean CHADS 2 score depicted for PMSS covers the major bleeding population only. Please note that these were not head-to-head studies and no direct comparisons can be made. IMS Disease Analyzer Figure 3: Persistence rates observed in nonvalvular atrial fibrillation (NVAF) patients with rivaroxaban, dabigatran and VKAs in the IMS Disease Analyzer database (49), the XANTUS study (9) and the Dresden NOAC registry (48) analyses. VKA: Vitamin K antagonist. Thrombosis and Haemostasis Supplement 2/2016 Schattauer 2016

5 Beyer-Westendorf et al. Update on rivaroxaban real-world evidence S17 the label was not followed. All patients had NVAF and were newly started on rivaroxaban, and followed up for 1 year or until 30 days after stopping treatment. The majority of patients (80.8 %, 3608/4464) received doses in accordance with the label. Investigators observed that patients receiving off-label doses of rivaroxaban experienced less favourable outcomes, which was found to be related to both inappropriate dosing and/or baseline patient characteristics (16). These findings highlight the importance of recommended label dosing and that various approved rivaroxaban doses can be supported by clinical and real-world evidence. Treatment persistence in XANTUS remained high over the 1 year study period, with 80 % of patients remaining on rivaroxaban therapy ( Figure 3). A total of 75.1 % of rivaroxaban patients (5096/6785) reported to their physicians that they were very satisfied or satisfied with their treatment, and the primary reason for premature discontinuation (7.9 % of all patients) was the occurrence of an AE (9). XALIA: Real-world rivaroxaban use for the treatment of symptomatic recurrent VTE in patients with DVT ± PE XA inhibition with rivaroxaban for Long-term and Initial Anticoagulation in venous thromboembolism (XALIA) is a prospective NIS conducted in hospitals and community care centres in 21 countries to investigate the treatment of symptomatic deep-vein thrombosis (DVT) with rivaroxaban or standard anticoagulation therapy (parenteral/vka or parenteral only) (17, 18). In August 2013, following the approval by the European Medicines Agency (EMA) of rivaroxaban for the treatment of pulmonary embolism (PE), the study protocol was amended to allow patients with DVT and concomitant PE into the study, while patients with isolated PE were still ineligible ( Table 2) (17). The main aim of the XALIA study was to confirm the results of the EINSTEIN DVT study in the real-world population. The propensity score-adjusted analysis included 2505 and 2010 rivaroxaban and standard anticoagulation patients, respectively. The incidence of recurrent venous thromboembolism (VTE) was 1.4 % and 2.3 % for the rivaroxaban group and the standard anticoagulation group, respectively (hazard ratio [HR] 0.91; 95 % confidence interval [CI] ; p=0.72) (17), a nonsignificant reduction in all-cause mortality for the rivaroxaban group compared with standard anticoagulation (0.4 % vs 3.4 %, respectively; HR 0.51; 95 % CI ; p=0.07) and a nonsignificant reduction in major bleeding (0.8 % vs 2.1 %, respectively; HR 0.77; 95 % CI ; p=0.44). In the unadjusted analysis, there were no fatal bleeding events in the rivaroxaban group and two fatal bleeding events in the standard anticoagulation group. The incidence of treatment-emergent AEs, in addition to those comprising the primary outcome during the study, was similar between the two groups (the incidence of blood and lymphatic system disorders was 1 % for both groups, and for gastrointestinal disorders was 7 % vs 6 % for rivaroxaban and standard anticoagulation, respectively) (17). Of note, patient characteristics were different between groups and patients treated with rivaroxaban were younger, and fewer had underlying cancer or concomitant PE than those who received standard anticoagulation therapy. However, when these differences were subject to propensity score-adjusted analyses, covariates across the groups were balanced and, in part, corrected selection bias. Data from XALIA were also indicative of potential economic benefits with rivaroxaban owing to shorter hospital stays compared with standard anticoagulation therapy (propensity score-adjusted analysis: 5.0 days vs 7.7 days, respectively) (17), a similar outcome to that observed in analyses from EINSTEIN DVT and EINSTEIN PE studies (19). In XALIA, the incidence of both symptomatic recurrent VTE and major bleeding observed were similar to or lower than those noted in EINSTEIN DVT (unadjusted analysis; recurrent VTE: 1.4 % vs 2.1 %, respectively; major bleeding: 0.7 % vs 0.8 %, respectively) (17, 20), supporting real-world use of rivaroxaban. XALIA will be discussed in further detail in the accompanying article, Spotlight on real-world evidence for the treatment of DVT: XALIA by Ageno et al. Other NIS are also underway, including the Rivaroxaban Observational Safety Evaluation (ROSE) study, which is a questionnaire-based, post-authorisation, observational safety specialist cohort study, covering England and Wales. The 3-year study aims to monitor and evaluate the short-term (first 3 months) safety of rivaroxaban use prescribed by specialists in secondary care in patients with approved indications requiring anticoagulation vs an alternative anticoagulant therapy (N=1700 per group) (21, 22). The study is estimated to be completed by April 2016, and no data have been published to date. Registries Registries prospectively capture information on patients with a particular condition registered at a specific centre or across multiple centres. As well as adding to the current body of knowledge by monitoring a particular disease and its management in a broad range of patients, they provide opportunities to compare and contrast practice-specific findings, and provide insights to better understand therapeutic approaches and outcomes (23). GARFIELD-AF: Global real-world treatment patterns in patients with non-valvular AF Initial key data from Global Anticoagulant Registry in the FIELD Atrial Fibrillation (GARFIELD-AF; Table 2) (24) showed that adherence to evidence-based AF guidelines remains poor: 40.7 % of patients with a CHA 2 DS 2 -VASc score 2 did not receive guideline-recommended anticoagulant prophylaxis (25). Physician choice was the deciding factor for not giving VKAs in 48.3 % of cases, for reasons including patient compliance concerns, bleeding risk and fall risk (25). Moreover, it was shown that anticoagulant use may not align with a patient s stroke risk, where ~75 % of patients with CHADS 2 and CHA 2 DS 2 -VASc scores of 0 had received antithrombotic or antiplatelet therapy (26).

6 S18 Beyer-Westendorf et al. Update on rivaroxaban real-world evidence International normalised ratio (INR) control was shown to have a clinically relevant impact on severe adverse outcomes, where patients with poorly controlled INR had higher unadjusted rates of stroke/se, major bleeding and all-cause mortality (27). Results from cohorts 1 and 2 demonstrated that only 25 % of VKAtreated patients had a frequency in range (FIR) 70 % (43 % had an FIR 60 %) (27). It was also shown that when time in the therapeutic range (TTR) values of >60 % or >70 % were explored as indicators of acceptable or good control in patients with NVAF, rates of stroke/se, major bleeding and all-cause mortality were higher when using both TTR cut-offs. However, increasing TTR from 60 % to 70 % demonstrated a marked difference in adverse outcomes (28). Patterns of anticoagulant use have also been evaluated in GAR- FIELD-AF and demonstrate the increasing use of NOACs with time (29). In cohorts 1 3 (N=17,475) in Europe, 51.0 % and 17.0 % of patients were administered a VKA or a NOAC at enrolment, respectively. Out of all patients receiving NOACs (N=2979), 47.2 % of patients received a factor Xa inhibitor at baseline. The uptake of NOACs increased across all countries included in the analysis, but varied considerably. For instance, at 12 months, NOAC use was as low as 0.9 % in Finland and as high as 53.3 % in Belgium. By the end of the enrolment period, NOAC use had increased to 2.6 % in Finland and 58.0 % in Belgium (29). Overall, cohort 1 3 anticoagulant use increased in cardiology and internal medicine care settings, which was attributed to increased total anticoagulation use (30). This increase in NOAC uptake is promising, while the observed country variations in this uptake may highlight the variances in availability and arrangements for reimbursement. Despite the availability of effective antithrombotic strategies, the risk of death remains high in patients with NVAF. At 0 24 months, cohorts 1 and 2 demonstrated that all-cause mortality was the most frequent major event in more than 17,000 newly-diagnosed patients with AF (3.83 % per person-year), exceeding the rate of stroke/se (1.25 % per person-year) and major bleeding (0.70 % per person-year). The event rates were substantially higher at 0 12 months (event rates for all-cause mortality, stroke/se and major bleeding were 4.15 % 1.43 % and 0.83 % per person-year, respectively) (31). In cohorts 1 3, additional 1-year outcomes from more than 28,000 patients with AF demonstrated an association of Table 3: Definition of the five-factor ORBIT risk score for bleeding (39). O R B I T Variable Older (75 years or older) Reduced haemoglobin (<13 mg/dl in men and <12 mg/dl in women), haematocrit (<40 % in men and <36 % in women) or history of anaemia Bleeding history Insufficient kidney function (egfr <60 mg/dl/1.73 m 2 ) Treatment with an antiplatelet agents egfr: Estimated glomerular filtration rate. Points comorbidities with increasing mortality, stroke/se and major bleeding. Patients with moderate-to-severe chronic kidney disease (CKD) and those with a history of myocardial infarction (MI) had a higher mortality rate than the overall population (9.4 % [HR 2.07; 95 % CI ] and 6.9 % [HR 1.69; 95 % CI ], respectively, compared with 4.0 %) (32). Overall, GARFIELD-AF is a large collaborative registry that has provided clinically important insights surrounding the management of AF nationally and globally. GARFIELD-VTE: Global real-world treatment patterns in patients with VTE Global Anticoagulant Registry in the FIELD-Venous Thromboembolism Events (GARFIELD-VTE, Clinicaltrials.gov identifier NCT ) (33) is a global, prospective, observational, multicentre registry that will evaluate the acute and longterm management and outcomes in patients with symptomatic DVT or PE treated in a real-world setting with both traditional standard of care and NOACs (all treatment patterns are covered, i. e. no treatment exclusion). GARFIELD-VTE will provide further understanding on the use of anticoagulation across different disease areas and healthcare systems. The registry will run as two prospective cohorts ( Table 2) (34). ORBIT-AF I and II: Global real-world treatment patterns in patients with AF Initial key data from Outcomes Registry for Better Informed Treatment of Atrial Fibrillation I (ORBIT-AF I; Table 2) provided a number of insights into the management of AF (35). More recently, ORBIT-AF was used as the basis for a contemporary community-based cohort analysis. Data showed that as many as 61.8 % of patients with AF were symptomatic and 16.5 % had impaired quality of life through severe or disabling symptoms (European Heart Rhythm Association [EHRA] 3 4). During follow-up, AF symptoms were associated with higher risk of hospitalisation but not mortality (36). Only 10 % (95 % CI 9 11 %) of patients receiving long-term warfarin were within the therapeutic range (INR ) in a 6-month period, and 90 % (95 % CI %) of those patients were proposed to have 1 INR value outside of the therapeutic range in the subsequent year, highlighting that few patients are truly stable on warfarin (37). Estimating stroke and bleeding risks are difficult as the risk of bleeding during anticoagulation is not homogeneous, and various clinical risk factors have been identified that are associated with incremental bleeding risk (38). This can lead to some clinicians failing to estimate stroke/bleeding risks accurately. A range of factors independently associated with major bleeding in patients taking oral anticoagulant (OAC; over a median follow-up of 2 years) were identified to create a simple, numerical bedside risk score, the five-factor ORBIT bleeding score with varied assigned point values (39) ( Table 3). Among the 7411 ORBIT-AF patients taking OAC, the rate of major bleeding observed was 4.0 per 100 personyears and major bleeding rates increased with increasing risk score. In a sensitivity analysis, the five-item score performed well Thrombosis and Haemostasis Supplement 2/2016 Schattauer 2016

7 Beyer-Westendorf et al. Update on rivaroxaban real-world evidence S19 at predicting ICH (C-index 0.69; 95 % CI ). The predictive accuracy of the ORBIT risk score was similar to other established bleeding risk scores (HAS-BLED [Hypertension, Abnormal renal and liver function, Stroke, Bleeding, Label INR, Elderly, Drugs or alcohol] and ATRIA [anticoagulation and risk factors in atrial fibrillation]), suggesting its usefulness as a clinical decisionmaking aid in routine practice (39). Owing to the conflicting recommendations on the optimal approach to heart rate control in patients with AF, ORBIT-AF investigated rate control and subsequent outcomes in 2812 outpatients with permanent AF (40). Patients were shown to maintain relatively low resting heart rates: 99 % had resting heart rates <110 beats per minute (bpm) and 70 % were <80 bpm. Investigators found that a heart rate >65 bpm was associated with worse symptom class and lower survival rates, even after adjusting for baseline clinical factors (all-cause mortality for each 5 bpm increase above 65 bpm; adjusted HR 1.10; 95 % CI ; p<0.0001). The data support current American College of Cardiology/American Heart Association (ACC/AHA) guideline recommendations for strict rate control, yet clinical trials to determine optimal rate control are warranted (40). Preliminary results from Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II (ORBIT-AF II, NCT identifier: NCT ; Table 2) published in 2014 showed that, at the time, NOAC use was steadily increasing in patients with existing and newly diagnosed AF in the US, with rivaroxaban being used in the majority of these patients (41). In patients with new-onset AF, 32 % were prescribed rivaroxaban, while 10 % and 9.4 % received apixaban and dabigatran, respectively (compared with 29 % who were prescribed warfarin). In patients with established AF who switched to NOACs, 66 % received rivaroxaban, compared with 26 % and 8.1 % for apixaban and dabigatran, respectively (41). Dresden NOAC registry: Real-world outcomes in German patients with non-valvular AF or VTE As of October 2015, 2941 patients had been enrolled in the Dresden NOAC registry ( Table 2) with 2053, 537 and 348 receiving rivaroxaban, dabigatran and apixaban, respectively (42, 43). Data from the Dresden NOAC registry supports that switching from a VKA to rivaroxaban is easy and reliable. Of 716 patients included in the analysis, 590 were switched from VKA to rivaroxaban (82.4 %; of these, 442 had AF and 148 had VTE) and 126 patients were switched to dabigatran (17.6 %; all had AF). At day 30 after switching, the rates of major cardiovascular (CV) events (0.8 %; all events occurring in patients with AF) and major bleeding (0.3 %; similar for both AF and VTE cohorts) were low (44). A further analysis from Dresden NOAC registry provided evidence that peri-interventional NOAC management (evaluated in 656 rivaroxaban-treated patients, 203 dabigatran-treated patients and 4 apixaban-treated patients) is simple and, without heparin bridging, results in low complication rates (43) across all NOACs. CV (4.6 %; 95 % CI ) and major bleeding complications (8.0 %; 95 % CI ) were highest after major procedures (procedures with relevant tissue trauma and high bleeding risk, such as open pelvic, abdominal and thoracic surgery, brain surgery, major orthopaedic and trauma surgery, vascular surgery). In contrast, the much more common minor procedures (procedures with little tissue trauma, but relevant bleeding risk, such as cataract surgery, endoscopy, dental extraction, and hernia repair) resulted in low complication rates, indicating that peri-interventional short-term interruption of NOAC in daily care can be safely managed (43). The real-world effectiveness and safety of rivaroxaban has been validated by the Dresden NOAC registry. In a cohort of 1204 patients with AF prospectively followed over a mean of days (± days), the combined endpoint of stroke/tia/se occurred at a rate of 2.03 per 100-patient years (intention-to-treat analysis; 95 % CI ) or 1.7 per 100-patient years (on-treatment analysis) (45). On-treatment major bleeding occurred at a rate of 3.0 per 100-patient years. Of all bleeding events observed during rivaroxaban therapy, only 6.1 % (66/1082) were ISTH-defined major bleeding events, which were mostly managed through conservative measures (62.1 %, 41/66) (15). More recently, the management and outcome of survivors of major bleeding relating to several NOACs was investigated in 2771 Dresden NOAC registry patients (46). The most common bleeding sites were GI (37 %), followed by diffuse bleeding during or after surgery (15.7 %), intracranial (11 %), skin/mucosal (9.4 %), intraocular (8.7 %), genitourinary (7.9 %), and intra-articular bleeding (6.3 %). A total of 85 cases led to hospitalisation and 31 bleeding events occurred during hospital stays. At day 30 after major bleeding, 63 % (N=80) of patients were restarted with OAC (NOAC or VKA). Interestingly, these patients exhibited a significantly lower rate of the combined endpoint of thromboembolism or recurrent major bleeding and a significantly lower rate of mortality, compared with those who did not restart OAC (46), reinforcing the potential benefits of continued OAC even in those who experience a major bleeding event (46). Rates of rivaroxaban treatment discontinuation were also analysed and were shown to occur in a total of 277 patients during followup (12.0 per 100-patient years) (45), which compares favourably with the discontinuation rate in the dabigatran cohort (25.8 per 100 patient-years [95 % CI ]) (47). During follow-up, the overall persistence with rivaroxaban therapy was 81.5 % ( Figure 3) (48). Overall, the Dresden NOAC registry continues to provide important insights on many aspects of real-world rivaroxaban safety, but also adherence and persistence patterns that augment our understanding of real-world rivaroxaban use from the perspective of the patient. Database analyses Database analyses provide valuable insights on management issues and outcomes from large established patient cohorts, and can be longitudinal or cross-sectional in nature (4). Such analyses examine retrospective data, but increasingly provide prospective insights on topics such as patient quality of life and longer term

8 S20 Beyer-Westendorf et al. Update on rivaroxaban real-world evidence outcomes, which may help address areas of improvement in patient care (4). A number of ongoing claims and electronic medical record (EMR) databases describe key information on NOAC use in daily practice, including long-term safety, patient adherence and persistence and epidemiological data on patients with VTE (14, 49 51). PMSS: Safety profile of rivaroxaban in patients with non-valvular AF The protocol for Post-Marketing Surveillance Study (PMSS) was designed by Janssen in collaboration with the US Food and Drug Administration (FDA; Table 2). The study analyses are being conducted by Health ResearchTx, LLC and data are compiled from the US Department of Defense (DoD) Military Health System (MHS) (14). Between January 2013 and March 2014, 27,467 rivaroxaban patients with NVAF were identified within the MHS database and the real-world rate of major bleeding with rivaroxaban was recorded as 2.86 per 100 personyears (496 major bleeding events in 478 patients [95 % CI ]) (14), using the validated Cunningham algorithm that closely approximates the ISTH major bleeding definition (14, 52). Of the patients with major bleeding, 63.2 % had been treated with rivaroxaban 20 mg Q. D. (14, 53), followed by 32.2 % and 4.6 % who received rivaroxaban 15 mg Q. D. and 10 mg Q. D., respectively. It was shown that patients who experienced major bleeding were older than those in the non-major bleeding group (mean age: 78.4 years vs 75.7 years), and had a higher prevalence of comorbidities, including hypertension (95.6 % vs 75.8 %), coronary artery disease (64.2 % vs 36.7 %), heart failure (48.5 % vs 23.7 %), and renal disease (38.7 % vs 16.7 %). The majority of bleeding events were GI (88.5 %), followed by intracranial (7.5 %). Fatal bleeding outcomes were shown to be reassuringly low (0.08 per 100 person-years [95 % CI ]) (14). While the results cannot be directly compared with those from clinical trials of rivaroxaban (due to reasons including study design differences, patient population, inclusion and exclusion criteria, bleeding definitions, etc.), the real-world incidence of major bleeding for rivaroxaban is consistent with that reported in ROCKET AF (13), and this database study provides valuable complementary safety data associated with rivaroxaban use in the post-marketing setting (14). Continuing investigations from PMSS will focus on the more detailed characterisations of real-world bleeding rates with rivaroxaban and associated risk factors. The strongest risk factors identified to date include increased age, anaemia, prior GI bleeding, heart failure, and vascular disease (nested case-control study; p< for all) (54). REVISIT-US: Evaluating ischaemic stroke and ICH in patients with non-valvular AF Using the US Truven Health MarketScan claims database, the Real-world EVIdence on Stroke prevention In patients with atrial Fibrillation in the United States (REVISIT-US) study includes claims data from 30,988 patients from January 2012 to October 2014 ( Table 2) (55). Preliminary data demonstrated that patients treated with rivaroxaban (N=11,411) were associated with a 47 % reduction in ICH (HR 0.53; 95 % CI ) and a 29 % decrease in ischaemic stroke (HR 0.71; 95 % CI ) compared with warfarin (N=11,411). For rivaroxaban and warfarin, respectively, the rate of ischaemic stroke was 0.54 % and 0.83 % per year, and the rate of ICH was 0.49 % and 0.96 % per year (55). These results are generally consistent with findings from ROCKET AF and XAN- TUS, confirming the benefit-risk profile of rivaroxaban, as well as highlighting the importance of balancing safety and efficacy in patients with NVAF. Studies in the IMS Disease Analyzer The retrospective IMS Disease Analyzer database contains data on 10 million patients in Germany, the UK, France, and Austria ( Table 2) (56). Two separate studies using data from IMS Disease Analyzer have described the clinical effectiveness of rivaroxaban vs VKAs in patients with NVAF (RELIEF) (50) and the persistence and adherence of rivaroxaban, dabigatran and VKAs in patients with NVAF (49) ( Table 2). Figure 4: Kaplan-Meier curves for time to primary composite endpoint for the RELIEF study (50). Primary endpoint was time to composite of ischaemic stroke, transient ischaemic attack, intracerebral haemorrhage, other nontraumatic intracranial haemorrhage including subdural haemorrhage, and myocardial infarction within 1 year of treatment initiation. P-value from log-rank test. HR: Hazard ratio; CI: Confidence interval; VKA: Vitamin K antagonist. Thrombosis and Haemostasis Supplement 2/2016 Schattauer 2016

9 Beyer-Westendorf et al. Update on rivaroxaban real-world evidence S21 Clinical outcomes with rivaroxaban vs VKAs in patients with non-valvular AF The REal-LIfe Evidence on Stroke Prevention in Patients with AF Fibrillation (RELIEF) study forms part of a retrospective database analysis in German outpatients or in German primary care using the IMS Disease Analyzer database (50). The objective was to compare the effectiveness and safety of newly-initiated rivaroxaban or VKA in patients with NVAF. Following propensity score-matching, 1039 rivaroxaban and 1039 VKA users not previously experiencing a primary event were followed up for a maximum of 360 days (mean age ~74, CHA 2 DS 2 -VASc ~3.9, ATRIA ~2.1). The incidence of the primary composite endpoint (ischaemic stroke, TIA, ICH, other non-traumatic ICH [including subdural haemorrhage] and MI) was also significantly lower in rivaroxaban-treated patients compared with those treated with VKA (1.97 % vs 3.68 %/year) (HR 0.536; 95 % CI ; p=0.0245; Figure 4) (50). RELIEF observed fewer ischaemic strokes (0.69 % vs 1.58 %/year) and fewer ICH events (0.1 % vs 0.29 %/year) with the rivaroxaban group compared with the VKA group (50). By establishing real-world use of rivaroxaban in patients with NVAF, RELIEF supports XANTUS outcomes (9), and adds to the existing rivaroxaban real-world evidence in this setting. Further analysis into effectiveness data is required to fully understand real-world outcomes between newly-initiated rivaroxaban and VKA therapy in patients with NVAF (50). Persistence and adherence of rivaroxaban in patients with non-valvular AF The objective of this analysis was to evaluate treatment persistence with and adherence to rivaroxaban, dabigatran and VKAs in primary care patients with NVAF (49). Patients were followed up for up to 360 days (N=7265 and N=3785, respectively). After 360 days, persistence remained significantly higher with rivaroxaban (53.1 %) and dabigatran (47.3 %) compared with VKAs (25.5 %) (rivaroxaban and dabigatran vs VKAs: p<0.001; Figure 3). Higher persistence was associated with male sex and diabetes, while lower persistence was associated with higher age, renal impairment and concomitant use of antiplatelet drugs. Similar results were observed throughout the follow-up period (49). High adherence (Medication Possession Ratio [MPR] 0.80) was observed in 61.4 % of rivaroxaban users and in 49.5 % of dabigatran users (means of 0.76 [95 % CI ] for rivaroxaban users, and 0.67 [95 % CI ] for dabigatran users [p<0.001]) (49). Overall, using robust sensitivity analyses, data from IMS Disease Analyzer supports the favourable persistence and adherence profile of rivaroxaban in patients with NVAF in routine clinical practice. Summary and conclusion By providing insights from actual clinical scenarios, real-world data complements RCT data and allows for the validation of the safety and effectiveness profiles of therapies such as rivaroxaban in the general population (3). NIS form an important part of clinical and product development programmes by answering critical questions and providing a vast amount of information that can be applied in routine clinical practice. XANTUS, the first published, large, international, prospective, observational study of a NOAC in stroke prevention in patients with NVAF, reaffirms the safety and efficacy of rivaroxaban observed in ROCKET AF. The risk profile of patients in XANTUS was lower than that observed in ROCKET AF (mean CHADS 2 score: 2.0 vs 3.5), which together support rivaroxaban use across the full risk score spectrum (9, 13). Results from XALIA supported findings observed in the EINSTEIN DVT trial, where the low bleeding incidences were observed: rates of major bleeding between the rivaroxaban and enoxaparin/vka groups were 0.8 % vs 1.2 %, respectively (HR 0.65; 95 % CI ; p=0.21) and fatal bleeding events were 1 vs 5 cases, respectively (20). XANTUS and XALIA now accompany Xarelto in the prophylaxis of post-surgical venous thromboembolism after elective major orthopaedic surgery of hip or knee (XAMOS), which investigated the safety and effectiveness of rivaroxaban in patients following major orthopaedic surgery of the hip or knee vs other pharmacological VTE prevention in routine clinical practice (57), to provide a comprehensive validation programme of rivaroxaban safety in large heterogeneous patient groups (9, 17, 58). Specific limitations with NIS include the observational nature, enrolment bias, and challenges when conducting global studies (e. g. different stages of the life cycle in different countries) (59). Registries are beneficial tools for effectively managing resources, improving patient well-being, and efficiently delivering quality patient care (60). International and local registries, including GARFIELD-AF, ORBIT-AF I and II and Dresden NOAC, are addressing the gaps in our knowledge and highlight that the management of thromboembolism continues to be suboptimal in certain situations (25, 37, 44). However, they can be labour-intensive to initiate, launch and maintain. Other limitations include source data verification, endpoint adjudication, controlled vs single arm, patient, physician and study-based selection bias, and underreporting of endpoint events (61). Nonetheless, these studies clearly demonstrate a shift from traditional anticoagulants to NOACs and that rivaroxaban is a viable option for the management of patients with NVAF or VTE in a real-world setting. Database analyses provide valuable insights on management issues and outcomes from large established patient cohorts, such as patient quality of life and longer term outcomes, that may help address patient care issues (4). Real-world findings from REVISIT- US, RELIEF and PMSS support findings from ROCKET AF and XANTUS, providing complementary data associated with rivaroxaban use in the post-marketing setting. Limitations associated with EMR and claims database analyses can include restricted generalisability, complexity, coverage and benefit restrictions, and lack of coverage when utilising claims records (62). Inadequate claims database/emr system design and improper use may lead to biased findings, which may put information integrity, patient record safety and quality of care at risk (63). Additionally, as these

10 S22 Beyer-Westendorf et al. Update on rivaroxaban real-world evidence data originate from routine clinical practice, its use for epidemiological analyses requires extensive data processing, and a good understanding of how the data were originally recorded and stored (51). However, a wealth of accessible and representative data that can be generated will help improve health information exchange between different stakeholders and provide experts with representative snapshots of real-world patients and their risk patterns. By 2015, the rivaroxaban research programme included more than 275,000 patients in clinical trials and real-world settings across a wide range of treatment settings. Data from Europe (Dresden NOAC registry), the US (ORBIT-AF), and globally (GARFIELD-AF) show that NOAC use is increasing, and that rivaroxaban is a widely-used agent (29, 30, 41, 44). NIS data (XANTUS and XALIA) (9, 17) and database analyses (PMSS, REVISIT-US, RELIEF) reaffirm the safety and efficacy of rivaroxaban previously observed in RCTs (14, 48, 51, 55), and that better persistence and adherence was seen with rivaroxaban in patients with NVAF in routine clinical practice compared with that observed in RCT (XANTUS, IMS Disease Analyzer) (49). It must be noted that retrospective persistence assessments cannot be compared to prospective studies, and findings from retrospective persistence analyses should only be used in relation to comparator treatments within the same study. It is expected that real-world evidence will continue to validate rivaroxaban usage in large patient populations across a wide range of risk profiles and comorbidities that reflect everyday clinical practice in order to help improve patient care. Acknowledgements The authors would like to acknowledge Jaya Shumoogam at Inspired Science, who provided editorial support with funding from Bayer Pharma AG. The author CAPT S. Tamayo would also like to thank the Navy and the Marine Corps Public Health Center for its support during the conduct of PMSS. Conflicts of interest All authors confirm that they have had full access to data and contributed to drafting of the paper. J. Beyer-Westendorf has received research grants from Bayer, Boehringer Ingelheim and Pfizer, and has served as a consultant to and has received honoraria from Bayer, Boehringer Ingelheim, Daiichi Sankyo and Pfizer. A.J. Camm has served as a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Pfizer, Sanofi, Johnson & Johnson, Boston Scientific and St. Jude Medical. C.I. Coleman has served as a consultant and/or has received research grants from Bayer Pharma AG, Janssen Scientific Affairs LLC, Boehringer Ingelheim Pharmaceutical Inc., Portola Pharmaceuticals and Pfizer. CAPT S. Tamayo reports no financial interests. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the US Government. CAPT S. Tamayo is a military service member. This work was prepared as part of her official duties. Title 17 U. S. C. 105 provides that Copyright protection under this title is not available for any work of the United States Government. Title 17 U. S. C. 101 defines a US Government work as a work prepared by a military service member or employee of the US Government as part of that person s official duties. References 1. Revicki DA, Frank L. Pharmacoeconomic evaluation in the real world. Effectiveness versus efficacy studies. 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