Background
Atrial fibrillation (AF) is the most common type of sustained cardiac arrhythmia, and its prevalence rises with age, with about 18% of patients older than 80 years being affected [
1]. Nonvalvular AF (NVAF) is strongly associated with increased morbidity and mortality related to ischemic stroke and systemic thromboembolism [
2,
3]. The risk of stroke in AF patients is about fivefold higher than in the non-AF population [
4], and AF-related strokes are generally more severe, with increased risk of death and disability compared to strokes from other causes [
5]. Elderly patients with AF are at higher risk of stroke than younger AF patients [
6,
7]. Indeed, age ≥ 75 years is a significant risk factor comparable to a history of stroke for the assessment of stroke risk by the CHA
2DS
2-VASc score [
8]. Prevention of stroke is therefore imperative in AF patients, particularly in elderly patients.
Oral anticoagulation (OAC) with vitamin K antagonists (VKA) has traditionally been the mainstay for stroke prevention in AF based on the robust clinical evidence of their efficacy in preventing stroke or systemic embolism and reducing mortality [
9]. However, VKAs have several known limitations, including the risk of major bleeding complications, especially intracranial hemorrhage, many food and drug interactions, and the need for frequent coagulation monitoring due to their narrow therapeutic window. Direct-acting oral anticoagulants (DOACs) targeting thrombin or factor Xa emerged as a welcome addition for stroke prevention in AF. These agents have predictable pharmacodynamic effects, allowing fixed dosing without the need for anticoagulation monitoring [
10]. DOACs, such as rivaroxaban, dabigatran, apixaban and edoxaban, have demonstrated to be noninferior to warfarin in stroke prevention without an increased risk of major bleeding [
11‐
15]. Based on their favorable efficacy, safety profile and convenience of use, DOACs are recommended over VKAs for stroke prevention in most patients with NVAF [
16].
Adequate selection of antithrombotic therapy for stroke prevention is critical for improving the clinical outcome of patients with NVAF. Several clinical practice guidelines have been developed to guide the management of AF patients, providing clinicians with recommendations on individualization of treatment based on the patient’s characteristics [
16,
17]. However, the implementation of guideline recommendations in routine clinical practice may be suboptimal. OAC is still underused in AF patients who are at high risk of stroke, and many patients are instead treated with antiplatelet agents or do not receive antithrombotic treatment [
18,
19]. Accordingly, despite the higher risk of stroke and bleeding in elderly NVAF patients [
20], anticoagulation has been traditionally underused in this population mainly due to the high frequency of associated comorbidities, including cardiovascular and kidney disease, multiple drug therapy, and concerns about cognitive impairment and risk of falls and bleeding [
21].
To date, limited data are available on the clinical management of NVAF patients, particularly in those patients attended in the internal medicine setting, where these patients are typically managed. There is therefore a need to identify current therapies used for stroke prevention and the factors that may guide the selection of treatment in the real-world setting. A better understanding of treatment patterns and factors potentially influencing treatment strategy is crucial to know whether clinical practice is in line with treatment recommendations of the current guidelines. Knowledge about the clinical management of patients with NVAF in clinical practice may improve OAC utilization for stroke prevention and outcomes.
Based on this background, we conducted a cross-sectional study to describe the demographic, functional, and clinical characteristics of patients with NVAF attending internal medicine departments in Spanish hospitals and the potential factors associated with antithrombotic treatment patterns.
Discussion
The present study assessed the demographic, functional, and clinical characteristics associated with antithrombotic treatment patterns in a large real-life population of patients with NVAF. The median age of patients was about 80 years, and most patients had permanent NVAF, with a median disease duration of over four years. As expected, this elderly population had a high comorbidity burden, particularly cardiovascular risk factors and disease, a very high thromboembolic risk and a moderate to high risk of bleeding. Most patients were autonomous and had no cognitive impairment. Patients with worse functional status and worse prognosis in terms of survival were those with more advanced age and with a higher risk of stroke and bleeding.
Despite being a population comprised of elderly patients with a high comorbidity burden, we found that the vast majority of patients (95%) were receiving antithrombotic treatment due to their high thromboembolic risk. Most patients received VKA treatment (60%) while DOACs were given in less than one-quarter of patients. Of note, antiplatelet therapy alone was prescribed in less than 7% of patients with NVAF in routine clinical practice.
Older age is a common reason given for not prescribing anticoagulation [
20,
28]. Thus, the high use of OAC shown in this real-world analysis (88%) was especially interesting, since 75% of patients were older than 75 years and 30% of patients were aged ≥ 85 years. This study has therefore highlighted that age alone was not considered as a contraindication for anticoagulation. The underuse of OAC in elderly patients is mainly due to overestimation of the risk of bleeding in these patients [
29]. However, the benefit of stroke prevention outweighs the potential increased risk of bleeding in these patients [
30,
31], in whom a higher net clinical benefit has been demonstrated compared to the younger population due to their higher thromboembolic risk [
32]. We found a substantial increase in the use of OAC in elderly patients compared to prior studies conducted in octogenarian AF patients in Spain, where only half of the patients received anticoagulation [
33]. This difference may suggest changes in physicians’ perceptions of the benefits and risks of OAC for older NVAF patients based on the available evidence demonstrating its benefit in this population [
20,
34].
Of note, the percentage of patients who received no antithrombotic treatment in our series (4.7%) was similar to that previously reported in the European population of the GLORIA-AF registry (4.1%) [
35]. However, compared to other European studies, our analysis showed a significantly lower proportion of untreated patients [
36,
37]. A higher rate of untreated patients has also been reported among elderly patients in the internal medicine setting in Spain (13.8%) [
38].
Although a history of prior bleeding has traditionally been associated with anticoagulation under-prescription in elderly patients [
39], bleeding history was not identified as a factor contributing to anticoagulation underuse in our study. Indeed, a high HAS-BLED score should not be a reason for non-prescription of anticoagulation but rather a tool to identify and control modifiable bleeding risk factors to reduce the risk of bleeding [
40,
41].
Antiplatelet therapy has traditionally been used instead of anticoagulation to prevent the risk of bleeding despite the demonstrated greater efficacy of anticoagulant treatment over antiplatelet agents without increasing major bleeding [
42]. Nevertheless, we found that the use of antiplatelet therapy alone (7%) was notably lower than that previously reported in primary care (20%) [
43]. Interestingly, antiplatelet therapy users were less frequent compared to prior national studies in elderly inpatients (about 18%) [
38,
44]. Indeed, we found that compared to outpatients, the proportion of hospitalized patients receiving antiplatelet therapy was higher, probably because these patients are more likely to have frailty and more comorbidity compared to outpatients and thus may not be considered optimal candidates for anticoagulation [
28].
Of note, institutionalized patients and those with total or partial dependence for daily activities, who were older and with higher thromboembolic and bleeding risk, were primarily treated with antiplatelets, which were also preferentially used in patients with functional disability and worse prognosis. These findings, therefore, suggest that there might be functional and prognostic factors driving the selection of antiplatelet therapy alone over OAC. Indeed, the univariate analysis showed that institutionalization, dependence for daily activities, 1-year mortality risk assessed by the PROFUND index, and life expectancy (physician’s clinical judgment) were factors significantly associated with preferential use of antiplatelet therapy over OAC. However, among these factors, only 1-year mortality risk was retained in the multivariate model, which showed that poor prognosis (intermediate or high risk) was a factor contributing to OAC non-prescription in favor of antiplatelet therapy alone.
This real-world assessment has also highlighted that the type of NVAF appears to be a factor that has played an essential role in the underuse of OAC in NVAF. In this regard, we found that patients with paroxysmal NVAF were more likely to receive antiplatelet therapy alone instead of OAC compared to patients with permanent NVAF in line with prior reports [
1,
35,
45]. The underuse of OAC in favor of antiplatelet therapy in patients with paroxysmal NVAF could be due to the perception of a lower thromboembolic risk associated with this type of NVAF [
46]. However, contrary findings regarding its impact on thromboembolic risk have been reported [
47,
48]. Nevertheless, according to current guidelines [
16], the decision concerning antithrombotic therapy should be based on the patient’s risk of stroke and bleeding, regardless of the type of NVAF.
Regarding the type of OAC, we found that a significant proportion of patients still received VKAs over DOACs despite guideline recommendations [
16]. The use of DOACs among patients receiving OAC (24.4%) was similar to that reported in Spanish studies conducted at the regional level during 2015 (24%) and 2011–2014 (25%) [
49] and the nationwide FANTASIIA registry (22%) [
50]. Thus, a substantial proportion of Spanish NVAF patients who could benefit from DOACs did not receive them, as recognized by experts [
51]. In addition, the preference for VKAs over DOACs may be due to the lack of available targeted DOAC reversal agents for patients with bleeding at the time of the study. Moreover, the prescription of DOACs can be challenging in Spain due to the restrictions for their use stated in the national Therapeutic Positioning Report (TPR) [
52] and the different administrative requirements of the Spanish Autonomous Communities. This study also found that the use of DOACs in Spain is still far behind other European countries, where an overall rate of DOAC prescription of approximately 50% [
35] has been reported. However, geographical differences have been found in prescription patterns [
36,
53,
54].
We found that neither the functional characteristics nor the prognosis (PROFUND index) or morbidity were associated with the use of DOACs. Nevertheless, preferential use of VKAs over DOACs was found among institutionalized patients, probably due to a more controlled environment which may enhance VKA treatment adherence and might avoid unacceptable risks derived from poor anticoagulation control. There appear to be sociodemographic factors driving DOAC selection, such as gender and educational level. Thus, educational level was identified as an independent factor associated with the use of DOACs, with a preference of these agents over VKAs in more educated patients, probably also with a higher income, in line with prior reports [
55]. This may be explained by better access of patients with a high educational level to the available information on new oral anticoagulants, which may influence treatment decision for stroke prevention. In addition, patients with longer disease duration were also more likely to receive VKA therapy over DOACs probably because prescription of DOACs may have only increased over the past few years due to current guidelines recommendation [
16]. A prior history of stroke was also associated with a higher likelihood of receiving DOACs according to the European recommendations [
16].
DOAC prescription has been traditionally limited by renal function, especially in elderly patients whose renal function is often unstable and affected by concomitant comorbidities and hospitalizations [
56,
57]. However, abnormal renal function was not identified as a factor contributing to DOAC non-prescription, in contrast to other reports in the primary care setting [
49]. Indeed, renal impairment should not be a limitation to DOAC prescription and reduced dose regimens of DOACs are approved for use in moderate and severe chronic kidney disease.
The main limitations of this study are due to the research design. This was a cross-sectional study which included a mixed incident and prevalent NVAF population; new starters and switchers from antithrombotic therapy, who were selected from a large sample of hospitals in Spain. However, it is noteworthy that this study did not aim to focus on treatment patterns, such as switching or discontinuation. In addition, we must take into account the obvious limitations of a retrospective chart review that uses patients’ data already recorded in the medical charts for reasons other than research, including incomplete or unrecorded information. A further limitation that should be acknowledged is the unequal number of patients in each group defined by the therapeutic strategy used for NVAF management. However, we should note that these groups were created according to clinical practice, given that patients could be receiving any treatment for NVAF when they were included in the study. Indeed, this study did not aim to assess the differences between these groups, and the comparisons made between them are exploratory and descriptive. Despite these limitations, this study provides valuable real-world data on the profile and treatment patterns of NVAF patients and grounds for discussion on whether antithrombotic treatment strategies are in line with guideline recommendations. Thus, the findings obtained in this analysis may be used to identify critical issues that should be improved in the management of NVAF patients, which might optimize patient care and outcomes. The strengths of this study include a highly representative population of non-selected elderly patients with NVAF in clinical practice, including inpatients and outpatients, attended in the internal medicine departments of more than 90 hospitals distributed homogeneously throughout the country. To our knowledge, this is the first and the most extensive study to assess the real-world characteristics of NVAF patients according to antithrombotic treatment after approval of DOACs in the internal medicine setting in Spain.
Acknowledgements
The authors would like to acknowledge the investigators of the PERFILAR study for its contribution to the study. We also thank Cristina Vidal and Antonio Torres from Dynamic Science (Spain) for their medical writing support, funded by Alliance Bristol-Myers Squibb/Pfizer, Spain. The authors would also like to thank Alliance Bristol-Myers Squibb/Pfizer for sponsoring/supporting the study.
Investigators of the PERFILAR study group (collaborators): Fernando Javier Sánchez Lora, Hospital Clínico Universitario Virgen de la Victoria, Málaga (Spain); Francisco Ibañez Bermúdez, Hospital Comarcal Infanta Margarita, Córdoba (Spain); Ana María Jurado Porcel, Complejo Hospitalario Regional Reina Sofía, Córdoba (Spain); Fernando Salgado Ordoñez, Complejo Hospitalario Regional de Málaga (Hospital Carlos Haya), Málaga (Spain); Francisco Rivera Civico, Complejo Hospitalario de Poniente, El Ejido, Almería (Spain); Luis Felipe Díez García, Hospital Torrecárdenas, Almeria (Spain); Fernando Jaén Águila, Hospital Universitario Virgen de las Nieves, Granada (Spain); Manuel Geraldía Lama, Hospital Virgen de las Montañas, Cádiz (Spain); Enrique Peral Gutiérrez-Ceballos, Complejo Hospitalario Virgen Macarena, Sevilla (Spain); Antonia Domínguez, Hospital Quironsalud Sagrado Corazón, Sevilla (Spain); Francisco Astudillo Martín, Hospital Infanta Luisa, Sevilla (Spain); Eduardo Aguilar, Hospital de Alcañiz, Teruel (Spain); Juan Ferrando Vela, Hospital Royo Villanova, Zaragoza (Spain); Alfonso García Aranda, Hospital Universitario Miguel Servet, Zaragoza (Spain); Mercedes Sánchez Cembellín, Hospital San Agustín, Avilés, Asturias (Spain); Juan Francisco López Caleya, Hospital de Cabueñes, Gijón (Spain); Sixto Ruiz, Hospital Comarcal de Inca, Islas Baleares (Spain); Melchor Rodríguez Gaspar, Hospital Universitario de Canarias, Santa Cruz de Tenerife (Spain); Alicia Conde Martel, Hospital Universitario de Gran Canaria Doctor Negrín, Las Palmas de Gran Canaria, Las Palmas (Spain); José Luis Hernández Hernández, Hospital Universitario Marqués de Valdecilla, Santander (Spain); Ismael Abascal Carrera, Hospital Comarcal de Laredo, Laredo (Spain); Alfonso Pérez del Molino Castellanos, Hospital Sierrallana, Torrelavega, Cantabria (Spain); Esther Fernández Pérez, Complejo Asistencial Universitario de León, León (Spain); Juan Carlos Martínez Acitores, Complejo Asistencial Universitario de Burgos, Burgos (Spain); Luis Miguel Seisdedos Cortes, Complejo Asistencial de Zamora, Zamora (Spain); Laura Abad Manteca, Hospital Universitario Rio Hortega, Valladolid (Spain); Marco Budiño Sánchez, Complejo Asistencial de Ávila, Ávila (Spain); José Javier Moreno Palomares, Complejo Asistencial de Segovia, Segovia (Spain); Inmaculada Coca Prieto, Hospital Santa Bárbara, Ciudad Real (Spain); Ana Isabel Muñoz, Hospital Nuestra Señora del Prado, Talavera de la Reina, Toledo (Spain); Ángel Sánchez Castaño, Hospital Virgen de la Salud, Toledo (Spain); Lola Ruiz Ribó, Hospital Virgen de la Luz, Cuenca (Spain); Jordi Mascaró, Hospital de la Santa Creu i Sant Pau, Barcelona (Spain); César Morcillo Serra, Hospital Cima Sanitas, Barcelona (Spain); Teresa Auguet Quintillá, Hospital Universitari Joan XXIII, Tarragona (Spain); Francesz Marimón, Hospital Universitari de Sant Joan de Reus, Tarragona (Spain); Joaquín Fernández Solá, Hospital Clinic i Provincial, Barcelona (Spain); José María Suriñach, Hospital Universitari Vall d'Hebron, Barcelona (Spain); Pablo Marchena, Parc Sanitari Sant Joan de Deu, Barcelona (Spain); Antoni Riera-Mestre, Hospital Universitari de Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona (Spain); Pedro Armario, Hospital de Sant Joan Despí Moisés Broggi, Sant Joan Despí, Barcelona (Spain); Ferrán García Bragado, Hospital Universitari de Girona Dr. Josep Trueta, Girona (Spain); Fátima del Molino, Hospital Quirón Salud del Vallés, Sabadell, Barcelona (Spain); Oscar Sacristán, Hospital Santa María, Alcalá de Henares, Madrid (Spain); Pere Almagro, Hospital Mutua de Terrassa, Terrassa, Barcelona (Spain); Conxita Falgà, Hospital de Mataró, Mataró, Barcelona (Spain); Francisco José Muñoz Rodríguez, Hospital de Mollet, Mollet del Vallès, Barcelona (Spain); Riesco, Hospital del Vendrell, El Vendrell, Tarragona (Spain); Jorge Romero Requena, Hospital Perpetuo Socorro, Badajoz (Spain); José Carlos Arévalo Lorido, Complejo Hospitalario Llerena-Zafra, Llerena, Badajoz (Spain); Manuela Chiquero Palomo, Complejo Hospitalario de Cáceres, Cáceres (Spain); Ana Isabel de la Cruz, Hospital Virgen del Puerto, Plasencia, Cáceres (Spain), Agustín Pijerro, Hospital Infanta Cristina, Badajoz (Spain); Elena Fernández Bouza, Complexo Hospitalario Universitario Arquitecto Marcide-Novoa Santos, Ferrol, A Coruña (Spain); Juan José González Soler, Complexo Hospitalario Universitario de Ourense, Ourense (Spain); Manuel Jesús Núñez Fernández, Complexo Hospitalario Universitario de Pontevedra, Pontevedra (Spain); Javier De La Fuente Aguado, Hospital de Povisa, Vigo, Pontevedra (Spain); José Antonio Díaz Peromingo, Complejo Hospitalario Universitario de Santiago, Santiago de Compostela, A Coruña (Spain); Julián Fernández Martín, Complejo Hospitalario de Vigo, Vigo, Pontevedra (Spain); Rafael Daroca Pérez, Complejo Hospital San Pedro, Logroño, La Rioja (Spain); Dr. Jesús Castiella Herrero, Fundación Hospital Calahorra, Calahorra, La Rioja (Spain); M. Cruz Carreño, Hospital Puerta de Hierro, Madrid (Spain); Jorge Gómez Cerezo, Hospital Universitario Infanta Sofía, San Sebastián de los Reyes, Madrid (Spain); José Carlos Pontes Navarro, Hospital Clínico San Carlos, Madrid (Spain); José Felipe Varona Arche, Hospital Universitario HM Montepríncipe, Boadilla del Monte, Madrid (Spain); Daniel Ferreiro López, Hospital Universitario 12 de octubre, Madrid (Spain); Benjamín Muñoz Calvo, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid (Spain); Jesús Manuel Casado Cerrada, Hospital Universitario de Getafe, Getafe, Madrid (Spain); María del Pilar Fidalgo Montero, Hospital Universitario del Henares, Coslada, Madrid (Spain); José Manuel Casas Rojo, Hospital Universitario Infanta Cristina, Parla, Madrid (Spain); Benjamín Herreros, Hospital Universitario Fundación Alcorcón, Alcorcón, Madrid (Spain); Guillermo Cuevas Tascón, Hospital Universitario Infanta Leonor, Madrid (Spain); Antonio Muiño Miguez, Hospitalario General Universitario Gregorio Marañón, Madrid (Spain); Jorge Marrero Francés, Hospital de Fuenlabrada, Fuenlabrada, Madrid (Spain); Nicolas Ortega, Hospital Virgen de la Arrixaca, El Palmar, Murcia (Spain); Javier Trujillo, Hospital Santa Lucía, Cartagena, Murcia (Spain); Julio Sánchez Álvarez, Complejo Hospitalario de Navarra, Pamplona, Navarra (Spain); Jose Ignacio Catalán Ramos, Policlínica San José, Vitoria, Álava (Spain); Francisco Javier Fresco Benito, Hospital Santa Marina, Bilbao, Vizcaya (Spain); Ainhoa Anuzita Alegría, Clínica Virgen Blanca, Bilbao, Vizcaya (Spain); Carlos Teruel, Hospital Gral. Castellón, Castellón de la Plana, Castellón (Spain); Arturo Artero Mora, Hospital Doctor Peset, Valencia (Spain); Pedro Moral, Hospital La Fe, Valencia (Spain); José Miguel Seguí Ripoll, Hospital Universitario San Juan, Alicante (Spain); Fernando Bonilla Rovira, Hospital General de Elche. Elche, Alicante (Spain); Ana Maestre Peiro, Hospital del Vinalopó, Elche, Alicante (Spain).