A continuous publication, open access, peer-reviewed journal ACCESS ONLINE ORIGINAL RESEARCH Clinical profile and management of rivaroxaban in patients with atrial fibrillation in routine practice in Spain: data from six nationwide studies Manuel Anguita MD1, Mariano de la Figuera MD2 , Alejandro I Pérez Cabeza MD3, Carmen Suarez Fernández MD4 1Cardiology Department, Hospital Universitario Reina Sofia, Córdoba, Spain; 2University Primary Care Health Center, Sardenya, Barcelona, Spain; 3Cardiology Department, Hospital Universitario Virgen de la Victoria, Málaga, Spain; 4Internal Medicine Department, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain Abstract prior cerebrovascular disease, but a lower thromboembolic risk Aims: To analyze the clinical profile and management of than those in the ROCKET-AF trial. In those studies with available patients with nonvalvular atrial fibrillation taking rivaroxaban in data, medication adherence and satisfaction with rivaroxaban routine practice in Spain. were high. Methods: Clinical data from the observational studies Conclusion: Bearing in mind differences according to the HEROIC (cardiology and hematology; n=1,727), EMIR clinical setting of each study, atrial fibrillation patients (cardiology; n=1,493), BRONCE-AP (primary care; n=133), taking rivaroxaban in Spain were elderly and had a high SILVER-AP (primary care; n=457), ALADIN (internal medicine and thromboembolic risk. Medication adherence and satisfaction neurology; n=249), and ESPARTA (internal medicine; n=110) of with rivaroxaban were high. patients taking rivaroxaban were analyzed. The clinical profile Keywords: atrial fibrillation, clinical practice, rivaroxaban, was compared with those of the XANTUS and ROCKET-AF ROCKET-AF, Spain, XANTUS. studies. Results: Overall, mean age was 74.9±9.4 years, CHA2DS2-VASc Citation score was 3.7±1.5, and 43.2% had a HAS-BLED score ≥3. Patients Anguita M, de la Figuera M, Pérez Cabeza AI, Suarez Fernández included in the HEROIC and EMIR studies were older and more C. Clinical profile and management of rivaroxaban in patients frequently had a creatinine clearance <50 mL/min and a higher with atrial fibrillation in routine practice in Spain: data from thromboembolic risk than those in the XANTUS study, and six nationwide studies. Drugs in Context 2019; 8: 212606. patients included in the ALADIN study were older and had more DOI: 10.7573/dic.212606 Introduction direct oral anticoagulants (DOACs) have at least a similar efficacy to VKA for the prevention of stroke, with a better safety Cardioembolic stroke in patients with atrial fibrillation (AF) is profile, mainly due to a lesser risk of intracranial hemorrhage.6,7 associated with significant morbidity and mortality.1 Prevention Fortunately, the introduction of DOACs in clinical practice of cardioembolic stroke is the main therapeutic approach for has increased the proportion of patients receiving oral improving prognosis among the AF population.2 Until the last anticoagulation for the prevention of stroke or systemic decade, antiplatelet agents and vitamin K antagonists (VKA) embolism in AF patients.8–10 Nevertheless, a significant were the antithrombotic therapies used for the prevention proportion of patients with a high thromboembolic risk remain of thromboembolic complications in nonvalvular AF (NVAF). without anticoagulant treatment, particularly elderly or frail However, due to the lack of efficacy of antiplatelet agents patients.10,11 for the prevention of stroke, and the limitations of VKA (e.g. periodic monitoring of anticoagulant effect, many food and Rivaroxaban was the first once-daily DOAC to be marketed. drug–drug interactions, slow onset and end of action), many The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition patients with AF have not traditionally received the appropriate Compared with Vitamin K Antagonism for Prevention of Stroke antithrombotic treatment.3–5 Not only clinical trials but also and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial studies performed in clinical practice have shown that overall, included 14,264 patients with NVAF at high risk of stroke. In Anguita M, de la Figuera M, Pérez Cabeza AI, Suarez Fernández C. Drugs in Context 2019; 8: 212606. DOI: 10.7573/dic.212606 1 of 11 ISSN: 1740-4398 ORIGINAL RESEARCH – Rivaroxaban in patients with atrial fibrillation drugsincontext.com this study, compared with warfarin, rivaroxaban was at least as with rivaroxaban in specialist practice (cardiology 70.8%, effective as warfarin for the prevention of stroke or systemic hematology 25.0%, and internal medicine 4.2%). It was embolism in patients with AF (non-inferior in the intention-to- performed to assess the impact of the 2013 Therapeutic treat population; superior with regard to safety in the as-treated Positioning Report of the Spanish Agency of Medicines and population), but with a marked reduction in the risk of critical Sanitary Products on the reasons for prescribing rivaroxaban bleeding (31%), fatal bleeding (50%), and intracranial hemorrhage in this population, the clinical profile of patients with (33%).12 Observational studies are important to ascertain NVAF treated with rivaroxaban, and how long it took to whether the results of the clinical trials can be applied to “real- access the treatment in National Health System hospitals in world”.13,14 Xarelto® for Prevention of Stroke in Patients with Atrial Spain.23 Fibrillation (XANTUS) was the first international prospective and The EMIR study is an ongoing postmarketing, observational, observational study of AF patients treated with rivaroxaban in multicenter, prospective, and nationwide study aimed to routine practice.15 A recent meta-analysis of “real-world” with identify those risk factors associated with major cardiovascular NVAF showed that compared with VKA, rivaroxaban significantly events among patients with NVAF who are under rivaroxaban reduced the risk of ischemic stroke by 17% and intracranial treatment for at least 6 months before inclusion and attend hemorrhage by 34%, with a similar risk of major bleeding.7 the cardiology units at Spanish hospitals and private clinics. Studies performed in routine practice may help determine in In this study, baseline data from the EMIR database have been which patients DOACs are being prescribed, and whether they reported.24,25 are being used properly. Although in recent years a number The BRONCE-AP study was an observational, cross-sectional, of studies on the use of rivaroxaban in clinical practice in and multicenter study that included patients with NVAF Spain have been published, these studies have been limited attended by primary care physicians from those autonomous to one single center or healthcare area or to a specific medical communities in which the primary care physician had to refer specialty.16–22 In this context, it is important to analyze the the patient to the specialist to start treatment with DOACs clinical management of rivaroxaban not limited to a specific (8 autonomous communities). Patients had to be on chronic area or specialty in Spain. The aim of this analysis was to treatment with anticoagulants, but on current treatment with determine the clinical profile and use in clinical practice of DOACs for at least 3 months.26,27 patients taking rivaroxaban in Spain, using data from the following studies: HEROIC (Perfil de pacientes con fibrilación The SILVER-AP study was an observational, cross-sectional, auricular novalvular tratados con rivaroxaban en España: la and multicenter study that included patients with NVAF desigualdad en el acceso a los anticoagulantes orales directos)23; attended by primary care physicians from those autonomous EMIR (Estudio observacional para la identificación de los factores communities in which the primary care physician could de riesgo asociados a eventos cardiovasculares mayores en prescribe DOACs directly (9 autonomous communities). pacientes con fIbrilación auricular no valvular tratados con un Patients had to be on chronic treatment with anticoagulants, anticoagulante oral directo Rivaroxaban)24,25; BRONCE-AP (Estudio but on current treatment with DOACs for at least observacional de corte transversal para evaluar el uso de recursos 3 months.26-28 y las características sociodemográficas y clínicas de los pacientes The ALADIN study was a cross-sectional and multicenter study diagnosticados de FANV con riesgo de ictus o embolia sistémica, aimed to validate the satisfaction questionnaire Anti-Clot- en tratamiento anticoagulante y que son atendidos en consultas Treatment Scale (ACTS) in outpatients with NVAF treated with de atención primaria)26,27; SILVER-AP (Estudio observacional de oral anticoagulants for at least 3 months and attended internal corte transversal para evaluar las características sociodemográficas medicine and neurology departments in Spain.29–31 y clínicas de los pacientes diagnosticados de FANV con riesgo The ESPARTA study was an observational, cross-sectional, and de ictus o embolia sistémica, que reciben tratamiento para el multicenter study in which patients aged ≥75 years with NVAF, control adecuado de su coagulación y que son atendidos en with stable treatment with oral anticoagulants for at least consultas de atención primaria)26–28; ALADIN (Validación del 3 months before inclusion and treated in internal medicine cuestionario ACTS en pacientes con Fibrilación Auricular tratados departments in Spain, were included. The aim of this study was con anticoagulantes orales en consultas de medicina interna y to evaluate, in this population, the adherence to the clinical neurología de España)29–31; ESPARTA (Estudio sobre el seguimiento practice recommendations of the ‘Therapeutic Positioning en la práctica clínica de las recomendaciones sobre el tratamiento Report of the Spanish Agency of Medicines and Sanitary con anticoagulantes orales en pacientes con fibrilación auricular de Products’.32–34 edad avanzada).32–34 In addition, our data were compared with those of the XANTUS study15,35 and the ROCKET-AF trial.12 All the studies were observational, and no specific diagnostic or therapeutic actions were taken for participating in them. Except for the EMIR study that was prospective, but only Methods baseline data were reported, the rest of the studies had a The HEROIC study was an observational, cross-sectional, cross-sectional design. All the studies were approved by the and multicenter study of patients with NVAF treated appropriate Clinical Research Ethics Committees, and in every Anguita M, de la Figuera M, Pérez Cabeza AI, Suarez Fernández C. Drugs in Context 2019; 8: 212606. DOI: 10.7573/dic.212606 2 of 11 ISSN: 1740-4398 ORIGINAL RESEARCH – Rivaroxaban in patients with atrial fibrillation drugsincontext.com study, all patients signed the written informed consent before Results inclusion. In the HEROIC and EMIR studies, a total of 1,727 and 1,493 In each study, data were collected from the medical history and patients taking rivaroxaban were included, respectively. In the physician interview and were entered into a specific electronic BRONCE-AP study, of 246 patients, 133 (54.1%) were taking case report form. Biodemographic data (age, sex); type of AF; rivaroxaban. In the SILVER-AP study, of 790 patients, 457 (57.8%) history of cerebrovascular disease; renal function (creatinine were taking rivaroxaban. In the ALADIN study, of 1,337 patients, clearance); and CHADS2, CHA2DS2-VASc, and HAS-BLED scores 249 (18.6%) were taking rivaroxaban (165 from the neurology were recorded. High thromboembolic risk was defined as a department and 84 from the internal medicine department). CHA2DS2-VASc score ≥2 and high bleeding risk as a HAS-BLED In the ESPARTA study, of 837 patients, 110 (13.1%) were score ≥3.2 taking rivaroxaban. Therefore, a total of 4,169 patients taking The clinical profiles of patients included in the HEROIC rivaroxaban were included for the final analysis of this study. and EMIR studies (patients attended by cardiologists or The clinical characteristics of the study population are reported hematologists) were compared with those of the XANTUS in Table 1. Overall, mean age was 74.9±9.4 years, 53.6% of study, and those of the ALADIN study (patients attended by patients were men, 43.2% had permanent AF, and 17.6% had internists and neurologists) with those of the ROCKET-AF trial prior cerebrovascular disease. In all, 93.7% of patients had a as they had a similar risk profile (i.e. age, thromboembolic risk), high thromboembolic risk (CHA2DS2-VASc ≥2), and 43.2% of respectively. patients had a high bleeding risk (HAS-BLED ≥3). In the HEROIC Anticoagulant treatment before starting rivaroxaban was and EMIR studies, 117 (6.8%) and 121 (8.1%) patients had recorded. Among patients who had taken VKA, the reasons valvular heart disease (other than significant mitral stenosis or for switching to rivaroxaban were analyzed. Adequate prosthetic valve). international normalized ratio (INR) control was defined as the Compared with the XANTUS study, patients included in the time in the therapeutic range ≥60% according to the direct HEROIC and EMIR studies were older (74.3±9.6 versus 71.5±10.0 method (percent time with INR values within therapeutic years; p<0.001), more commonly women (45.9 versus 40.8%; range) and ≥65% according to the Rosendaal method.36 p<0.001), and more frequently had permanent AF (36.7 Polymedication was defined as using five or more prescription versus 27.0%; p<0.001), a creatinine clearance <50 mL/min drugs at the moment of the visit. With regard to rivaroxaban (12.9 versus 9.1%; p<0.001), and a higher thromboembolic risk therapy, duration of treatment, the dosage prescribed, and (CHA2DS2-VASc ≥2: 92.7 versus 87.3%; p<0.001), but less prior medication persistence were recorded. Medication adherence cerebrovascular disease (13.5 versus 19.0%; p<0.001) (Table 2). was assessed at the moment of the study.37,38 Compared with the ROCKET-AF trial (rivaroxaban arm), patients Treatment satisfaction with rivaroxaban was determined with included in the ALADIN study were older (75.6±9.4 versus 73.0 the Anti-Clot Treatment Scale (ACTS) questionnaire. ACTS is a years; p<0.001), more commonly women (46.2 versus 39.7%; patient-reported questionnaire that includes 12 items about p=0.04), and had more prior cerebrovascular disease (64.3 the burdens of anticoagulant therapy and 3 items about the versus 54.9%; p=0.004), but a lower thromboembolic risk benefits of anticoagulant treatment. Patients are asked to (CHADS2 3.3±1.1 versus 3.5±0.9; p=0.005) (Table 3). report their experiences with anticoagulants during the last With regard to the antithrombotic treatment, 57.7% of our 4 weeks on a 5-point scale of intensity (from not at all -1- to patients took VKA before starting treatment with rivaroxaban, extremely -5-). The ACTS Burdens score ranges from 12 to 60 mainly acenocoumarol (89.5%). Poor INR control was the most points and the ACTS Benefits from 3 to 15 points. Higher scores common reason (68.9% of patients taking VKA) for switching in the ACTS Burdens indicate lesser burden (higher satisfaction) from VKA to rivaroxaban. Overall, the mean duration of with anticoagulant therapy and higher scores in the ACTS treatment with rivaroxaban at baseline was 14.1±11.5 months. Benefits represent higher benefit (higher satisfaction) with With regard to the dosage of rivaroxaban, 74.1% of patients anticoagulant treatment.29 were taking rivaroxaban 20 mg, and the remaining 25.9% rivaroxaban 15 mg. In the EMIR study, a total of 300 patients Statistical analysis (20.1%) had a creatinine clearance <50 mL/min; underdosing Quantitative variables were described with mean and standard was observed in 153 patients (10.4%), and overdosing in 121 deviation and qualitative variables as absolute (n) and relative patients (8.2%). Polymedication was reported in 75.0, 78.3, and (%) frequencies. In the bivariate analyses, to compare two means, 86.4% of patients included in the BRONCE-AP, ALADIN, and parametric (Student’s t-test) or non-parametric (Mann–Whitney ESPARTA studies, respectively. In all, 92.7% of patients were U test) statistical tests were performed based on the sample adherent to rivaroxaban in the study (Table 4). distribution. To compare percentages, the chi-square test or Compared with the XANTUS study, more patients included in Fisher test were used, according to the sample size. Statistical the HEROIC and EMIR studies were taking VKA before starting significance was set at a p-value <0.05. The statistical analysis treatment with rivaroxaban (51.4 versus 45.5%; p<0.001). The was performed using the SAS statistics package, version 9.4. dosage of rivaroxaban was similar among patients included Anguita M, de la Figuera M, Pérez Cabeza AI, Suarez Fernández C. Drugs in Context 2019; 8: 212606. DOI: 10.7573/dic.212606 3 of 11 ISSN: 1740-4398 ORIGINAL RESEARCH – Rivaroxaban in patients with atrial fibrillation drugsincontext.com Table 1. Clinical characteristics of patients taking rivaroxaban included in the different observational studies in Spain.* HEROIC23 EMIR24,25 BRONCE- SILVER- ALADIN29–31 Overall (n=1,727) (n=1,493) AP26,27 AP26–28 (n=249) (n=4,059) (n=133) (n=457) Age, years 74.4±9.6 74.1±9.7 76.1±8.5 78.9±8.0 75.6±9.4 74.9±9.4 Sex, male (%) 53.0 55.5 48.9 51.4 53.8 53.6 Permanent AF (%) — 36.7 42.9 64.6 — 43.2 Prior cerebrovascular disease (%) 14.8 12.0 19.5 20.6 64.3 17.6 CrCl <50 mL/min (%) 6.8 20.1 21.8 26.5 — 14.9 CHADS2, 2.1±1.2 1.9±1.2 2.3±1.4 2.6±1.2 3.3±1.1 2.2±1.2 High risk (≥2) (%) 67.9 — 71.4 80.5 — 70.6 CHA2DS2-VASc 3.6 ± 1.5 3.4±1.5 4.0±1.8 4.3±1.6 4.9±1.4 3.7±1.5 High risk (≥2) (%) 92.7 — 91.7 98.0 — 93.7 HAS-BLED 2.4 ± 0.9 1.5±1.0 1.9±1.0 2.3±1.0 2.4±1.3 2.0±1.0 High risk (≥3) (%) 45.6 — 26.3 39.2 — 43.2 AF, atrial fibrillation; CrCl, creatinine clearance. *Calculated with the available data for each study. CHADS2: Congestive heart failure, Hypertension, Age >75, Diabetes mellitus, prior Stroke; CHA2DS2-VASc: Congestive heart failure, Hypertension, Age ≥75, Diabetes mellitus, prior Stroke, Vascular disease, Age 65-74, Sex category (female); HAS-BLED: Hypertension, Abnormal liver/renal function, Stroke history, Bleeding history or predisposition, Labile INR, Elderly, Drug/alcohol usage. Table 2. Clinical characteristics of patients taking rivaroxaban included in the HEROIC, EMIR, and XANTUS studies*. HEROIC23 EMIR24,25 HEROIC + EMIR XANTUS study15 PHEROIC+EMIR (n=1,727) (n=1,493) (n=3,220) (n=6,784) versus XANTUS Age (years) 74.4±9.6 74.1±9.7 74.3±9.6 71.5+10.0 <0.001 Sex (male; %) 53.0 55.5 54.1 59.2 <0.001 Permanent AF (%) — 36.7 36.7 27.0 <0.001 Prior cerebrovascular disease (%) 14.8 12.0 13.5 19.0 <0.001 CrCl <50 mL/min (%) 6.8 20.1 12.9 9.1 <0.001 CHADS2 2.1±1.2 1.9±1.2 2.0±1.2 2.0+1.3 NS High risk (≥2) (%) 67.9 — 67.9 59.2 <0.001 CHA2DS2-VASc 3.6±1.5 3.4±1.5 3.5±1.5 3.4+1.7 0.004 High risk (≥2) (%) 92.7 — 92.7 87.3 <0.001 HAS-BLED 2.4±0.9 1.5±1.0 2.0±0.9 — — High risk (≥3) (%) 45.6 — 45.6 — — AF, atrial fibrillation; CrCl, creatinine clearance; NS, not significant; *Calculated with the available data for each study. CHADS2: Congestive heart failure, Hypertension, Age >75, Diabetes mellitus, prior Stroke; CHA2DS2-VASc: Congestive heart failure, Hypertension, Age ≥75, Diabetes mellitus, prior Stroke, Vascular disease, Age 65-74, Sex category (female); HAS-BLED: Hypertension, Abnormal liver/renal function, Stroke history, Bleeding history or predisposition, Labile INR, Elderly, Drug/alcohol usage. in the XANTUS study and the HEROIC and EMIR studies. and more patients were taking rivaroxaban 20 mg (79.4 versus Compared with the HEROIC and EMIR studies, in the ROCKET-AF 76.8%; p=0.03) (Table 5). In the XANTUS study and ROCKET- trial (rivaroxaban arm), more patients were taking VKA before AF trial, 79.9 and 85.7% of patients remained on rivaroxaban starting treatment with rivaroxaban (62.3 versus 51.4%; p<0.001), therapy after 329 days and 1 year of treatment, respectively. Anguita M, de la Figuera M, Pérez Cabeza AI, Suarez Fernández C. Drugs in Context 2019; 8: 212606. DOI: 10.7573/dic.212606 4 of 11 ISSN: 1740-4398 ORIGINAL RESEARCH – Rivaroxaban in patients with atrial fibrillation drugsincontext.com internal medicine, neurology, and hematology) throughout Table 3. Clinical characteristics of patients Spain, treated with rivaroxaban for the prevention of stroke or included in the ALADIN study and systemic embolism. In our study, patients were elderly (mean ROCKET-AF trial*. age 75 years), nearly 50% of patients were women, and up to 18% of patients had prior cerebrovascular disease. In addition, ALADIN29–31 ROCKET- PALADIN thromboembolic risk was high, and more than 40% of patients (n=249) AF12 versus had a high bleeding risk. Compared with the XANTUS study,15 (rivaroxaban ROCKET-AF arm) patients included in the HEROIC and EMIR studies were older, (n=7,131) had more frequently a creatinine clearance <50 mL/min, Age (years) 75.6±9.4 73.0 <0.001 and a higher thromboembolic risk, and compared with the ROCKET-AF study (rivaroxaban arm),12 patients included in the Sex 53.8 60.3 0.04 ALADIN study were older and had more prior cerebrovascular (male; %) disease, but a lower thromboembolic risk. Overall, our patients Permanent — 81.1 — had a lower thromboembolic and bleeding risk than those AF (%) included in the ROCKET-AF trial but a higher thromboembolic Prior 64.3 54.9 0.004 risk than those included in the XANTUS study.12,15 ROCKET- cerebrovascular AF was the clinical trial that included those patients with the disease (%) highest thromboembolic risk among all DOAC trials.39-41 When CrCl <50 mL/ — 20.6 — rivaroxaban was introduced in clinical practice, it was mainly min (%) prescribed in patients with a better clinical profile,13–15 or CHADS2 3.3±1.1 3.5±0.9 0.005 among patients with a high bleeding risk.22 However, as our High risk — 100 — (≥2) (%) study has shown, the experience with rivaroxaban has increased in routine practice, it is prescribed in different clinical settings, CHA2DS2-VASc 4.9±1.4 — — and its use has been extended to the entire AF population, High risk — 100 — (≥2) (%) regardless of the clinical profile of patients. Therefore, this study exhibits an accurate description of the clinical profile and HAS-BLED 2.4±1.3 — — High risk — 62.5 — management of NVAF patients taking rivaroxaban in Spain and (≥3) (%) may complement, in our country, the information provided by the ROCKET-AF trial and the XANTUS study. AF, atrial fibrillation; CrCl, creatinine clearance; *Calculated with the available data for each study. In the HEROIC and EMIR studies, between 7 and 8.1% of CHADS2: Congestive heart failure, Hypertension, Age patients had valvular heart disease.23–25 As is well known, >75, Diabetes mellitus, prior Stroke; CHA2DS2-VASc: DOACs are contraindicated in patients with AF and mechanical Congestive heart failure, Hypertension, Age ≥75, Diabetes prosthetic valves or moderate to severe mitral stenosis (usually mellitus, prior Stroke, Vascular disease, Age 65-74, Sex of rheumatic origin), but they can be used in patients with category (female); HAS-BLED: Hypertension, Abnormal other native valvular disease.42 Thus, a recent meta-analysis liver/renal function, Stroke history, Bleeding history or predisposition, Labile INR, Elderly, Drug/alcohol usage. of four phase III AF clinical trials has shown that the overall efficacy and safety of DOACs were independent of the presence of valvular heart disease.43 Satisfaction of treatment with rivaroxaban using the ACTS scale With regard to the antithrombotic treatment, in our study, nearly was specifically analyzed in the BRONCE-AP, SILVER-AP, and 58% of our patients were taking VKA before starting treatment ALADIN studies. Overall, in our study, the mean ACTS burden with rivaroxaban. This percentage was higher than that and benefit scores were 52.3±6.9 and 12.1±2.2, respectively. In reported in other studies performed in Europe or the United the SILVER-AP study, the mean ACTS burden and benefit scores States in routine practice, but lower than that in the ROCKET-AF were higher among patients taking rivaroxaban for 12 months trial.12,15,44,45 This is because in Spain, the reimbursement for or more compared with those patients taking rivaroxaban for the initial prescription of DOACs is limited in the majority of the less than 12 months (53.1±6.5 versus 50.3±8.0; p<0.001, and autonomous communities to some specific conditions, such as 12.2±2.3 versus 11.8±2.3; p=0.008, respectively). In the XANTUS poor INR control or a high intracranial bleeding risk.46 In fact, in study, after switching from VKA to rivaroxaban, the ACTS burden our study, poor INR control was the most common reason (69% and benefit scores significantly increased at month 3 (Table 6). of patients taking VKA) for switching from VKA to rivaroxaban. This is very relevant, as in Spain, up to 40–50% of patients taking VKA have inadequate anticoagulation control. Considering that Discussion approximately 30% of all oral anticoagulants prescribed in Spain Our study included more than 4,100 patients with NVAF, correspond to DOACs and the remaining 70% to VKA, these data attended by different specialties (i.e. primary care, cardiology, strongly suggest that DOACs are underused in Spain.47,48 Anguita M, de la Figuera M, Pérez Cabeza AI, Suarez Fernández C. Drugs in Context 2019; 8: 212606. DOI: 10.7573/dic.212606 5 of 11 ISSN: 1740-4398 ORIGINAL RESEARCH – Rivaroxaban in patients with atrial fibrillation drugsincontext.com Table 4. Antithrombotic treatment of patients included in different observational studies in Spain.* HEROIC23 EMIR24,25 BRONCE- SILVER- ESPARTA32–34 Overall* (n=1,727) (n=1,493) AP26,27 AP26–28 (n=110) (n=133) (n=457) Previous use of VKA (%) 57.0 44.9 89.5 97.2 39.1 57.7 Warfarin 15.1 — 1.7 3.2 4.7 10.5 Acenocoumarol 84.9 — 98.3 96.8 95.3 89.5 Switch due to poor INR control (%) 64.8 68.2 83.1 75.7 67.4 68.9 Previous use of heparin (%) 6.2 2.2 10.5 2.6 0 4.2 Previous use of other DOACs (%) 2.9 2.7 0 0 1.8 2.3 Duration of treatment with — — 14.7±10.8 13.5± 11.1 15.6±14.1 14.1±11.5 rivaroxaban (months) Rivaroxaban (%) 20 mg — 76.8 69.9 70.2 59.1 74.1 15 mg — 22.0 30.1 29.8 40.9 25.9 Adherence to rivaroxaban treatment (%)† — — 97.9 97.2 68.2 92.7 DOACs, direct oral anticoagulants; INR, international normalized ratio; VKA, vitamin K antagonists. *Calculated with the available data for each study. †The Haynes–Sackett test was applied in the BRONZE-AP and SILVER-AP studies. The Morisky–Green test was applied in the ESPARTA study. Table 5. Antithrombotic treatment of patients included in the HEROIC, EMIR, and XANTUS studies and ROCKET-AF trial.* HEROIC23 EMIR24,25 HEROIC + XANTUS PHEROIC+ ROCKET-AF12 PHEROIC+EMIR (n=1,727) (n=1,493) EMIR study15 EMIR versus (rivaroxaban versus ROCKET-AF (n=3,220) (n=6,784) XANTUS arm) (n=7,131) Previous use of VKA (%) 57.0 44.9 51,4 45.5 <0.001 62.3 <0.001 Warfarin 15.1 — 15.1 — — — — Acenocoumarol 84.9 — 84.9 — — — — S witch due to poor INR 64.8 457 (68.2) — — — — control (%) Previous use of heparin (%) 6.2 2.2 4.3 3.2 0.004 — — Previous use of other DOACs (%) 2.9 2.7 2.8 3.2 NS 0 <0.001 Duration of treatment with — — — 11.0±3.8 — 23.6 — rivaroxaban (months) Rivaroxaban (%) 20 mg — 76.8 76.8 78.7 NS 79.4 0.03 15 mg — 22.0 22.0 21.3 NS 20.6 NS DOACs, direct oral anticoagulants; INR, international normalized ratio; NS, not significant; VKA, vitamin K antagonists. *Calculated with the available data for each study. Polymedication was reported in 75–86% of our patients. efficacy and safety of rivaroxaban were independent of Drug–drug interactions with rivaroxaban are uncommon. the number of concomitant drugs and the use of ≥1 In the ROCKET-AF trial, polymedication was associated with combined cytochrome P450 3A4 and P-glycoprotein a higher risk of bleeding but not of stroke. Importantly, the inhibitors.49 Anguita M, de la Figuera M, Pérez Cabeza AI, Suarez Fernández C. Drugs in Context 2019; 8: 212606. DOI: 10.7573/dic.212606 6 of 11 ISSN: 1740-4398 ORIGINAL RESEARCH – Rivaroxaban in patients with atrial fibrillation drugsincontext.com Table 6. Satisfaction of treatment with rivaroxaban in the BRONCE-AP, SILVER-AP, ALADIN, and XANTUS studies.* BRONCE-AP26,27 SILVER-AP26–28 ALADIN29–31 Overall XANTUS study35 (n=133) (n=457) (n=249) (n=1,291) Baseline At month 3 Burden scale 54.1± 6.0 51.4±7.5 54.6±6.2 52.3±6.9 50.5±8.4 54.4 <12 months of treatment — 50.3±8.0 — — ≥12 months of treatment — 53.1±6.5 — — Benefit scale 12.1± 2.3 12.0±2.3 12.4±2.1 12.1±2.2 10.3±2.7 11.4 <12 months of treatment — 11.8±2.3 — — ≥12 months of treatment — 12.2±2.3 — — *Calculated with the available data for each study. With regard to the suitability of dosage of rivaroxaban, in the of data recorded may diminish this risk. Of note, not all EMIR study, underdosing was observed in 10.4% of patients and variables could be recorded in all studies, and some analyses overdosing, in 8.2%.24 In the XANTUS study, of patients with a were not performed with the data of the six studies. In addition, creatinine clearance ≥50 mL/min, 15% received rivaroxaban 15 comparing our data with those of the XANTUS and the mg, and of patients with moderate or severe renal impairment, ROCKET-AF studies has some limitations, as these studies had 36% of patients received rivaroxaban 20 mg.15 Remarkably, a different design and inclusion criteria. However, due to the underdosing with rivaroxaban has not been associated with importance of these studies about the use of rivaroxaban, these an increased risk of stroke.50 However, despite the observation comparisons may be of interest. Finally, the results of our study that prescription of inappropriate doses seems lower with can be applied only to patients with a similar clinical profile and rivaroxaban compared with other DOACs, it is common in health care system. real-world clinical practice,51 and this may have a negative impact on outcomes.7 Therefore, it is mandatory to prescribe the appropriate dosage of DOACs according to the clinical Conclusion characteristics of the patients. NVAF patients taking rivaroxaban for the prevention of stroke Medication persistence was high in the XANTUS study in routine practice in Spain were elderly and had a high (80%) and in the ROCKET-AF trial (86% at year one).12,15 In thromboembolic risk, and more than 40% of patients had a recent retrospective study, approximately 96 and 91% of a high bleeding risk. Patients included in the HEROIC and patients remained on rivaroxaban therapy after 1 and 2 years EMIR studies were older and had more renal insufficiency of treatment, respectively.17 In our study, adherence with and a higher thromboembolic risk than those in the XANTUS rivaroxaban was high (93%) at the moment of being included study, and patients included in the ALADIN study were older in the study. Medication persistence is essential in patients and had more prior cerebrovascular disease, but a lower with chronic conditions, such as AF. All these data indicate thromboembolic risk than those in the ROCKET-AF trial that medication persistence and adherence are high among (rivaroxaban arm), suggesting that in Spain, rivaroxaban is patients taking rivaroxaban in routine practice. prescribed in a wide range of NVAF patients. Approximately 58% of patients were taking VKA before starting treatment with Not only AF but also anticoagulation treatment is associated rivaroxaban, with poor INR control being the main reason for with poorer quality of life.52 Although it has been reported switching. However, according to guidelines, treatment naïve that satisfaction with treatment is high among patients with patients with NVAF should start anticoagulant treatment with AF chronically anticoagulated with VKA,53 the XANTUS study DOACs, instead of VKA. Overall, 74% of patients were taking demonstrated that switching from VKA to rivaroxaban was rivaroxaban 20 mg, and 26% rivaroxaban 15 mg. In the majority associated with an improvement of quality of life.35 In our of patients, rivaroxaban was properly prescribed, even better study, satisfaction with rivaroxaban was high (low burden and than with other DOACs, likely due to its high simplicity of use high benefit with anticoagulant treatment), particularly among (i.e. a single daily dose and dosage adjustment only according patients chronically anticoagulated. to renal function). Medication adherence and satisfaction with Although including data from different studies may increase rivaroxaban were high. All these data strongly suggest that the risk of bias, the high number of patients included rivaroxaban is a good alternative for the treatment of NVAF throughout Spain, the similar study designs, and the accuracy patients. Anguita M, de la Figuera M, Pérez Cabeza AI, Suarez Fernández C. Drugs in Context 2019; 8: 212606. DOI: 10.7573/dic.212606 7 of 11 ISSN: 1740-4398 ORIGINAL RESEARCH – Rivaroxaban in patients with atrial fibrillation drugsincontext.com Contributions: All authors contributed equally to the preparation of this review. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published. Disclosure and potential conflicts of interest: MA has received funding for consultancy services and lecturing from Bayer, Daiichi- Sankyo and Pfizer. MDLF has received funding from Bayer Hispania for designing and publishing SILVER and BRONZE studies. APC has no conflict of interest to declare. CSF has received funding for consultancy services and lecturing from Bayer, Daiichi-Sankyo and Pfizer. The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the authors is available for download at http://www.drugsincontext.com/wp-content/uploads/2019/09/dic.212606-COI.pdf Acknowledgments: Editorial assistance was provided by Content Ed Net, Madrid, Spain. Funding declaration: Editorial assistance was funded by Bayer Hispania. Copyright: Copyright © 2019 Anguita M, de la Figuera M, Pérez Cabeza AI, Suarez Fernández C. https://doi.org/10.7573/dic.212606. Published by Drugs in Context under Creative Commons License Deed CC BY NC ND 4.0, which allows anyone to copy, distribute, and transmit the article provided it is properly attributed in the manner specified below. No commercial use without permission. Correct attribution: Copyright © 2019 Anguita M, de la Figuera M, Pérez Cabeza AI, Suarez Fernández C. Published by Drugs in Context under Creative Commons License Deed CC BY NC ND 4.0. Article URL: https://www.drugsincontext.com/clinical-profile-and-management-of-rivaroxaban-in-patients-with-atrial-fibrillation-in-routine- practice-in-spain:-data-from-six-nationwide-studies/ Correspondence: Manuel Anguita, Hospital Universitario Reina Sofia, Ctra. Av. Menendez Pidal, s/n, 14004, Córdoba, Spain. manuelp.anguita.sspa@juntadeandalucia.es Provenance: submitted; externally peer reviewed. Submitted: 18 June 2019; Peer review comments to author: 13 August 2019; Revised manuscript received: 3 September 2019; Accepted: 9 September 2019; Publication date: 9 October 2019. Drugs in Context is published by BioExcel Publishing Ltd. Registered office: Plaza Building, Lee High Road, London, England, SE13 5PT. BioExcel Publishing Limited is registered in England Number 10038393. VAT GB 252 7720 07. For all manuscript and submissions enquiries, contact the Editor-in-Chief gordon.mallarkey@bioexcelpublishing.com For all permissions, rights and reprints, contact David Hughes david.hughes@bioexcelpublishing.com References 1. Alkhouli M, Noseworthy PA, Rihal CS, Holmes DR Jr. Stroke prevention in nonvalvular atrial fibrillation: a stakeholder perspective. J Am Coll Cardiol. 2018;71(24):2790–2801. https://doi.org/10.1016/j.jacc.2018.04.013 2. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J. 2016;37(38):2893–2962. https://doi.org/10.1093/eurheartj/ehw210 3. Suárez Fernández C, Formiga F, Camafort M, et al. Antithrombotic treatment in elderly patients with atrial fibrillation: a practical approach. BMC Cardiovasc Disord. 2015;15:143. https://doi.org/10.1186/s12872-015-0137-7 4. Wehbe RM, Yadlapati A. Underuse of oral anticoagulants for nonvalvular atrial fibrillation: past, present, and future. Tex Heart Inst J. 2016;43(4):287–290. https://doi.org/10.14503/THIJ-16-5785 5. Barrios V, Calderón A, Escobar C, de la Figuera M. Patients with atrial fibrillation in a primary care setting: Val-FAAP study. Rev Esp Cardiol (Engl Ed). 2012;65(1):47–53. https://doi.org/10.1016/j.recesp.2011.08.008 6. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014;383(9921):955–962. https://doi.org/10.1016/S0140-6736(13)62343-0 7. Escobar C, Martí-Almor J, Pérez Cabeza A, Martínez-Zapata MJ. Direct oral anticoagulants versus vitamin K antagonists in real-life patients with atrial fibrillation. A systematic review and meta-analysis. Rev Esp Cardiol (Engl Ed). 2019;72(4):305–316. https://doi.org/10.1016/j.rec.2018.03.009 8. Spence JD. Cardioembolic stroke: everything has changed. Stroke Vasc Neurol. 2018;3(2):76–83. https://doi.org/10.1136/svn-2018-000143 9. Pol D, Curtis C, Ramukumar S, Bittinger L. NOACs now mainstream for the use of anticoagulation in non-valvular atrial fibrillation in Australia. Heart Lung Circ. 2019;28(4):e40–e42. https://doi.org/10.1016/j.hlc.2018.03.010 10. Admassie E, Chalmers L, Bereznicki LR. Changes in oral anticoagulant prescribing for stroke prevention in patients with atrial fibrillation. Am J Cardiol. 2017;120(7):1133–1138. https://doi.org/10.1016/j.amjcard.2017.06.055 Anguita M, de la Figuera M, Pérez Cabeza AI, Suarez Fernández C. Drugs in Context 2019; 8: 212606. DOI: 10.7573/dic.212606 8 of 11 ISSN: 1740-4398 ORIGINAL RESEARCH – Rivaroxaban in patients with atrial fibrillation drugsincontext.com 11. Oqab Z, Pournazari P, Sheldon RS. What is the impact of frailty on prescription of anticoagulation in elderly patients with atrial fibrillation? A systematic review and meta-analysis. J Atr Fibrillation. 2018;10(6):1870. https://doi.org/10.4022/jafib.1870 12. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10): 883–891. https://doi.org/10.1056/NEJMoa1009638 13. Barón-Esquivias G, Marín F, Sanmartín Fernandez M. Rivaroxaban in patients with atrial fibrillation: from ROCKET AF to everyday practice. Expert Rev Cardiovasc Ther. 2017;15(5):403–413. https://doi.org/10.1080/14779072.2017.1309293 14. Barrios V, Escobar C. From clinical trials to clinical practice. Experience with rivaroxaban in the anticoagulant treatment of patients with non-valvular atrial fibrillation. Semergen. 2017;43(3):222–229. https://doi.org/10.1016/j.semerg.2016.01.016 15. Camm AJ, Amarenco P, Haas S, et al. XANTUS: a real-world, prospective, observational study of patients treated with rivaroxaban for stroke prevention in atrial fibrillation. Eur Heart J. 2016;37(14):1145–1153. https://doi.org/10.1093/eurheartj/ehv466 16. Martí E, Segado A, Pastor-Galán I, et al. Use of rivaroxaban for the prevention of stroke in patients with nonvalvular atrial fibrillation in Spain. Future Cardiol. 2018;14(3s):3–8. https://doi.org/10.2217/fca-2018-0020 17. Pérez Cabeza AI, González Correa JA, Chinchurreta Capote PA, et al. Drug persistence and outcomes in a cohort of patients with nonvalvular atrial fibrillation treated with rivaroxaban after 2 years of follow-up in clinical practice. Future Cardiol. 2018;14(3s):9–16. https://doi.org/10.2217/fca-2018-0021 18. Muñiz Lobato S, Tarrazo Tarrazo C, González Fernández E, Morán Alcalá M. Future Cardiol. 2018;14(3s):17–24. https://doi.org/10.2217/fca-2018-0022 19. Gavín Sebastián O, Izuzquiza Fernández M, Martínez Fernández R, Palomera Bernal L. Anticoagulation with rivaroxaban in a hematology unit: clinical profile, events and discontinuation rates in real-life patients with nonvalvular atrial fibrillation. Future Cardiol. 2018 May;14(3s):25–30. https://doi.org/10.2217/fca-2018-0023 20. Cerezo-Manchado JJ, Navarro-Almenzar B, Elvira-Ruiz G, et al. Effectiveness and safety of rivaroxaban in a cohort of 142 patients with nonvalvular atrial fibrillation treated with rivaroxaban for the prevention of stroke. Future Cardiol. 2018;14(3s):31–37. https://doi.org/10.2217/fca-2018-0024 21. Brun Guinda D, Callen García Ó, Ondiviela Pérez J, et al. Clinical profile, management and outcomes in a cohort of elderly and highly comorbid patients with nonvalvular atrial fibrillation treated with rivaroxaban in routine practice. Future Cardiol. 2018;14(3s):39–45. https://doi.org/10.2217/fca-2018-0025 22. Pimentel Quezada Y, Bonilla Palomas JL, Gámez López AL, et al. Has the clinical profile of patients with nonvalvular atrial fibrillation treated with rivaroxaban changed in the last 5 years of use? Future Cardiol. 2018;14(3s):47–53. https://doi.org/10.2217/fca-2018-0026 23. Peris Vidal J, Ferreiro Argüelles M, Hidalgo Urbano RJ, et al. Patients with non-valvular atrial fibrillation treated with rivaroxaban in Spain: unequal access to oral direct anticoagulants (HEROIC study). Cardiocore. 2018;53(4), 159–165. https://doi.org/10.1016/j.carcor.2018.04.002 24. Marín F, Rivera Caravaca JM, Esteve Pastor MA, et al. Atherothrombotic risk profile in patients with nonvalvular atrial fibrillation treated with rivaroxaban in Spain. Rev Esp Cardiol. 2018;71 (Suppl 1):A6009–151. 25. Sanmartín Fernández M, Anguita Sánchez M, Marín F, et al. Not adequate dosage of rivaroxaban according to creatinine clearance in nonvalvular atrial fibrillation. Data from a multicenter and prospective study. Rev Esp Cardiol. 2018;71 (Suppl 1):A6003–74. 26. de la Figuera M, Cinza S, Egocheaga I, Marín N, Prieto MA; SILVER BRONCE-AP Investigators. Clinical characteristics and management of patients with atrial fibrillation treated with direct oral anticoagulants according to blood pressure control. Hipertens Riesgo Vasc. 2018;35(4):e1–e9. https://doi.org/10.1016/j.hipert.2018.01.003 27. de la Figuera M, Prieto MA, Marín N, Egocheaga I, Cinza S; on behalf of the SILVER BRONCE-AP Investigators. Differences in the management of patients with atrial fibrillation according to whether primary care or the specialist initiates treatment with direct oral anticoagulants. The SILVER-AP and BRONCE-AP studies. Semergen. 2018;44(5):323–334. https://doi.org/10.1016/j.semerg.2017.09.005 28. de la Figuera M, Cinza S, Marín N, Egocheaga I, Prieto MA; on behalf og the SILVER-AP Investigators. Clinical characteristics of patients with atrial fibrillation treated with direct oral anticoagulants attended in primary care setting. The SILVER-AP study. Aten Primaria. 2018;50(6):359–367. https://doi.org/10.1016/j.aprim.2017.05.009 29. Suárez C, Pose A, Montero-Pérez-Barquero M, et al. Validation of satisfaction questionnaire ACTS in outpatients with atrial fibrillation treated with oral anticoagulants in Spain. ALADIN Study. Med Clin (Barc). 2016;147(5):192–198. https://doi.org/10.1016/j.medcli.2016.05.024 Anguita M, de la Figuera M, Pérez Cabeza AI, Suarez Fernández C. Drugs in Context 2019; 8: 212606. DOI: 10.7573/dic.212606 9 of 11 ISSN: 1740-4398 ORIGINAL RESEARCH – Rivaroxaban in patients with atrial fibrillation drugsincontext.com 30. Contreras Muruaga MM, Reig G, Vivancos J, et al. Factors associated with poor anticoagulation control with vitamin K antagonists among outpatients attended in internal medicine and neurology. The ALADIN study. Rev Clin Esp. 2018;218(7):327–335. https://doi.org/10.1016/j.rce.2018.04.020 31. Reig-Rosello G, Contreras MM, Suarez-Fernandez C, et al. Clinical profile and satisfaction with anticoagulated treatment in patients with non-valvular atrial fibrillation attended in Internal Medicine and Neurology departments of Spain. Rev Neurol. 2017;65(8):361–367. https://doi.org/10.33588/rn.6508.2017063 32. Suárez Fernández C, Mostaza JM, Castilla Guerra L, et al. Adherence to recommendations of the Therapeutic Positioning Report about treatment with oral anticoagulants in elderly patients with atrial fibrillation. The ESPARTA study. Med Clin (Barc). 2018;151(1):8–15. https://doi.org/10.1016/j.medcli.2017.07.025 33. Mostaza JM, Suárez Fernández C, Castilla Guerra L, et al. Type and doses of oral anticoagulants and adherence to anticoagulant treatment in elderly patients with atrial fibrillation: the ESPARTA study. J Comp Eff Res. 2018;7(3):223–232. https://doi.org/10.2217/cer-2017-0034 34. Suárez Fernández C, Castilla-Guerra L, Cantero Hinojosa J, et al. Satisfaction with oral anticoagulants in patients with atrial fibrillation. Patient Prefer Adherence. 2018;12:267–274. https://doi.org/10.2147/PPA.S152109 35. Coleman CI, Haas S, Turpie AG, et al. Impact of switching from a vitamin K antagonist to rivaroxaban on satisfaction with anticoagulation therapy: The XANTUS-ACTS Substudy. Clin Cardiol. 2016;39(10):565–569. https://doi.org/10.1002/clc.22565 36. Rosendaal FR, Cannegieter SC, Van der Meer FJ, Briët E. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost. 1993;69(3):236–239. PubMed PMID: 8470047 37. Haynes RB, Taylor DW, Sackett DL, Gibson ES, Bernholz CD, Mukherjee J. Can simple clinical measurements detect patient noncompliance? Hypertension. 1980;2(6):757–764. https://doi.org/10.1161/01.hyp.2.6.757 38. Morisky DE, Green LW, Levine DM. Concurrent and predictive validity of a self-reported measure of medication adherence. Med Care. 1986;24(1):67–74. PubMed PMID: 3945130 39. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139–1151. https://doi.org/10.1056/NEJMoa0905561 40. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981–992. https://doi.org/10.1056/NEJMoa1107039 41. Giugliano RP, Ruff CT, Braunwald E, et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093–2104. https://doi.org/10.1056/NEJMoa1310907 42. Steffel J, Verhamme P, Potpara TS, et al. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J. 2018;39(16):1330–1393. https://doi.org/10.1093/eurheartj/ehy136 43. Renda G, Ricci F, Giugliano RP, De Caterina R. Non-Vitamin K antagonist oral anticoagulants in patients with atrial fibrillation and valvular heart disease. J Am Coll Cardiol. 2017;69(11):1363–1371. https://doi.org/10.1016/j.jacc.2016.12.038 44. Yu AYX, Malo S, Svenson LW, Wilton SB, Hill MD. Temporal trends in the use and comparative effectiveness of direct oral anticoagulant agents versus warfarin for nonvalvular atrial fibrillation: A Canadian Population-Based Study. J Am Heart Assoc. 2017;6(11):pii: e007129. https://doi.org/10.1161/JAHA.117.007129 45. Eikelboom JW, Weitz JI. ‘Real world’ use of non-vitamin K antagonist oral anticoagulants (NOACs): lessons from the Dresden NOAC Registry. Thromb Haemost. 2015;113(6):1159–1161. https://doi.org/10.1160/TH15-02-0158 46. Therapeutic Positioning Report UT_ACOD/V5/21112016. Criteria and general recommendations for the use of direct oral anticoagulants in the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. https://www.aemps.gob.es/medicamentosUsoHumano/informesPublicos/docs/criterios-anticoagulantes-orales.pdf. [Last accessed July 20, 2018]. 47. Barrios V, Escobar C, Prieto L, et al. Anticoagulation control in patients with nonvalvular atrial fibrillation attended at primary care centers in Spain: The PAULA Study. Rev Esp Cardiol (Engl Ed). 2015;68(9):769–776. https://doi.org/10.1016/j.rec.2015.04.017 48. Anguita Sánchez M, Bertomeu Martínez V, Cequier Fillat Á; CALIFA study researchers. Quality of Vitamin K antagonist anticoagulation in Spain: prevalence of poor control and associated factors. Rev Esp Cardiol (Engl Ed). 2015;68(9):761–768. https://doi.org/10.1016/j.rec.2014.11.019 49. Piccini JP, Hellkamp AS, Washam JB, et al. Polypharmacy and the efficacy and safety of rivaroxaban versus warfarin in the prevention of stroke in patients with nonvalvular atrial fibrillation. Circulation. 2016;133(4):352–360. https://doi.org/10.1161/CIRCULATIONAHA.115.018544 50. Yao X, Shah ND, Sangaralingham LR, Gersh BJ, Noseworthy PA. Non-Vitamin K antagonist oral anticoagulant dosing in patients with atrial fibrillation and renal dysfunction. J Am Coll Cardiol. 2017;69(23):2779–2790. https://doi.org/10.1016/j.jacc.2017.03.600 51. Ruiz Ortiz M, Muñiz J, Raña Míguez P, et al. Inappropriate doses of direct oral anticoagulants in real-world clinical practice: prevalence and associated factors. A subanalysis of the FANTASIIA Registry. Europace. 2018;20(10):1577–1583. https://doi.org/10.1093/europace/eux316 Anguita M, de la Figuera M, Pérez Cabeza AI, Suarez Fernández C. Drugs in Context 2019; 8: 212606. DOI: 10.7573/dic.212606 10 of 11 ISSN: 1740-4398 ORIGINAL RESEARCH – Rivaroxaban in patients with atrial fibrillation drugsincontext.com 52. Badia X, Arribas F, Ormaetxe JM, Peinado R, de Los Terreros MS. Development of a questionnaire to measure health-related quality of life (HRQoL) in patients with atrial fibrillation (AF-QoL). Health Qual Life Outcomes. 2017;5:37. https://doi.org/10.1186/1477-7525-5-37 53. Escobar C, Barrios V, Prieto L, Lobos JM, Polo J, Vargas D; Paula Study Team. Perception of patients regarding burdens and benefits of vitamin K antagonists among patients with nonvalvular atrial fibrillation. Cardiovasc Hematol Agents Med Chem. 2018;16(2):106–113. https://doi.org/10.2174/1871525716666180608075834 Anguita M, de la Figuera M, Pérez Cabeza AI, Suarez Fernández C. Drugs in Context 2019; 8: 212606. DOI: 10.7573/dic.212606 11 of 11 ISSN: 1740-4398