ORIGINAL RESEARCH published: 02 May 2022 doi: 10.3389/fcvm.2022.856222 Impact of Integrated Care Management on Clinical Outcomes in Atrial Fibrillation Patients: A Report From the FANTASIIA Registry María Asunción Esteve-Pastor 1 , Martín Ruiz-Ortiz 2 , Javier Muñiz 3 , Inmaculada Roldán-Rabadán 4 , Déborah Otero 5 , Ángel Cequier 6 , Vicente Bertomeu-Martínez 7 , Lina Badimón 8 , Manuel Anguita 2 , Gregory Y. H. Lip 9,10† and Francisco Marín1* † on behalf of FANTASIIA investigators 1 Department of Cardiology, Hospital Clínico Universitario Virgen de la Arrixaca, CIBERCV, Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), Murcia, Spain, 2 Department of Cardiology, Hospital Universitario Reina Sofía, Córdoba, Spain, 3 Grupo de Investigación Cardiovascular, Departamento de Ciencias de la Salud e Instituto de Investigación Biomédica de A Coruña (INIBIC), CIBERCV, Universidade da Coruña, A Coruña, Spain, 4 Department of Cardiology, Hospital La Paz, Madrid, Spain, 5 ODDS, SL, A Coruña, Spain, 6 Department of Cardiology, Hospital de Bellvitge, CIBERCV, Barcelona, Spain, 7 Department of Cardiology, Hospital Universitario de San Juan, Alicante, Spain, 8 Cardiovascular Research Center Edited by: (CSIC-ICCC), Hospital de la Santa Creu i Sant Pau, CIBERCV, IIB-Sant Pau, Barcelona, Spain, 9 Liverpool Centre Jonathan Douxfils, for Cardiovascular Science, University of Liverpool and Liverpool Heart and Chest Hospital, Liverpool, United Kingdom, University of Namur, Belgium 10 Department of Clinical Medicine, Aalborg University, Aalborg, Denmark Reviewed by: Job Harenberg, Heidelberg University, Germany Background: An integrated and holistic approach is increasingly advocated in patients Håkan Wallen, with atrial fibrillation (AF), based on the “Atrial fibrillation Better Care (ABC) pathway: A, Karolinska Institutet (KI), Sweden Jordi Heijman, Avoid stroke with anticoagulation; B, better symptom management; C, cardiovascular Maastricht University, Netherlands and comorbidity risk management.” The aim of this study was to examine the prevalence *Correspondence: of adherence to each component of the ABC pathway and to analyze its impact on long- Francisco Marín term prognosis in the “real-world” cohort of AF patients from the FANTASIIA registry. fcomarino@hotmail.com † These authors share senior Methods: This prospective study included consecutive AF outpatients anticoagulated authorship with direct oral anticoagulants (DOAC) or vitamin K antagonists (VKA) from June 2013 Specialty section: to October 2014. From the ABC pathway, adherence to the “A criterion” was defined by This article was submitted to a time in the therapeutic range (TTR) ≥ 70% or correct dose with DOAC; “B criterion” Thrombosis, adherence was defined by a European Heart Rhythm Association (EHRA) Symptom a section of the journal Frontiers in Cardiovascular Medicine Scale I-II; and “C criterion” adherence was defined as optimized risk factors and Received: 16 January 2022 comorbidity management. Baseline features and embolic events, severe bleeding, and Accepted: 05 April 2022 all-cause and cardiovascular mortality rates up to 3 years of follow-up were analyzed, Published: 02 May 2022 and a Cox multivariate analysis was performed to investigate the role of each component Citation: Esteve-Pastor MA, Ruiz-Ortiz M, of the ABC pathway in predicting major events. Muñiz J, Roldán-Rabadán I, Otero D, Cequier Á, Bertomeu-Martínez V, Results: A total of 1,955 AF patients (age: 74.4 ± 9.4 years; 43.2% female patients) Badimón L, Anguita M, Lip GYH and were included in this study: adherence to A criterion was observed in 920 (47.1%) Marín F (2022) Impact of Integrated patients; adherence to B criterion was observed in 1,791 (91.6%) patients; and Care Management on Clinical Outcomes in Atrial Fibrillation adherence to C criterion was observed in 682 (34.8%) patients. Only 394 (20.2%) Patients: A Report From of the whole population had good control of AF according to the ABC pathway. the FANTASIIA Registry. Front. Cardiovasc. Med. 9:856222. After a median follow-up of 1,078 days (IQR: 766–1,113), adherence to A criterion doi: 10.3389/fcvm.2022.856222 was independently associated with reduced cardiovascular mortality [HR: 0.67, 95%CI Frontiers in Cardiovascular Medicine | www.frontiersin.org 1 May 2022 | Volume 9 | Article 856222 Esteve-Pastor et al. Integrated Approach in Atrial Fibrillation (0.45–0.99); p = 0.048] compared with non-adherence. Adherence to the B criterion was independently associated with reduced stroke [HR: 0.28, 95%CI (0.14–0.59); p < 0.001], all-cause mortality [HR: 0.49, 95%CI (0.35–0.69); p < 0.001], cardiovascular mortality [HR: 0.39, 95%CI (0.25–0.62); p < 0.001], and major adverse cardiovascular events (MACE) [HR: 0.41, 95%CI (0.28–0.62); p < 0.001] compared with non- adherence. AF patients with C criterion adherence had a significantly lower risk of myocardial infarction [HR: 0.31, 95%CI (0.15–0.66); p < 0.001]. Fully adherent ABC patients had a significant reduction in MACE [HR: 0.64, 95%CI (0.42–0.99); p = 0.042]. Conclusion: In real-world anticoagulated AF patients from FANTASIIA registry, we observed a lack of adherence to integrated care management of AF following the ABC pathway. AF managed according to the ABC pathway was associated with a significant reduction in adverse outcomes during long follow-up, suggesting the benefit of a holistic and integrated approach to AF management. Keywords: atrial fibrillation, patient adherence, risk factors, ABC-pathway, integrated approach INTRODUCTION with VKA (12) or a label-adherent correct dose of direct oral anticoagulants (DOACs). The “B criterion” refers to patient- Atrial fibrillation (AF) has emerged as a major public health centered symptom-directed decisions on rate or rhythm control; issue, and more than two-thirds of patients older than 70 years and the “C criterion” refers to control of cardiovascular risk will present with this disease, increasing hospital admissions factors and comorbidities, including lifestyle changes (11, 13). and direct and indirect healthcare costs (1). The presence of The aim of this study was to examine the prevalence of AF increases the risk of stroke, cardiovascular events, and adherence to each component of the ABC pathway and to analyze mortality (2). its impact on long-term prognosis in the “real-world” cohort of Both hospitalization and complications related with AF could AF patients from the FANTASIIA registry. be preventable with appropriate guideline-adherent care to reduce adverse outcomes in those patients (3). The concept of integrated care was developed by Wagner et al. (4) regarding MATERIALS AND METHODS the effective interventions for patients with chronic diseases highlighting five areas, namely, the use of evidence-based The study design of the FANTASIIA registry has been described therapies with planned care of interventions, reorganization earlier (14). FANTASIIA (Spanish Acronym for “Fibrilación of health systems, improved patient self-management support, Auricular: influencia del Nivel y Tipo de Anticoagulación Sobre increased access to expertise with multidisciplinary teams, and la Incidencia de Ictus y Accidentes hemorrágicos”) registry is greater availability of clinical information (3, 4). Such an an observational, prospective, national, and multicenter study integrated care approach can be extended to various clinical of clinical and demographic characteristics of Spanish AF settings (5, 6). In the case of AF, such an integrated and patients. In brief, the main objective of this study is to assess holistic approach is essential. AF management not only involves the incidence of thromboembolic and bleeding events in an oral anticoagulation for stroke prevention but also needs an unselected population of patients with AF, specifically, the improvement of AF symptomatology with rate or rhythm type of oral anticoagulant (VKA or DOACs) and quality of control, management of risk factors with targeted treatments, anticoagulation with VKAs. We excluded AF patients with or control of concomitant comorbidities to mitigate treatment valvular heart disease. When we refer to AF patients throughout burden (7, 8). Indeed, a multidisciplinary holistic approach to the article, we analyzed non-valvular atrial fibrillation patients, manage AF, including behavior changes and close follow-up, is but that term is deprecated according to the latest 2020 ESC associated with significantly lower cardiovascular outcomes and clinical guidelines (12) because it can be confusing. For that reduced medical costs (9, 10). reason, we only write “AF patients.” Such an integrated and holistic approach for the management of AF disease can be based on the “Atrial fibrillation Better Study Population Care” (ABC) pathway (11). The “A criterion” refers to Avoid Between June 2013 and March 2014, all outpatients with a stroke, i.e., identifying those patients who are truly at low confirmed diagnosis of paroxysmal, persistent, or permanent AF risk, who do not need oral anticoagulation, and who do not were prospectively enrolled. Patients included in the registry had use effective oral anticoagulation. When vitamin K antagonists been receiving OAC (VKA or DOACs) for at least 6 months (VKA) are used, a high time in therapeutic range (TTR) ≥ 70% is before enrollment. The study was conducted in 50 outpatient necessary for best effectiveness and safety of oral anticoagulation clinics by 80 investigators. To “simulate” true DOAC use during Frontiers in Cardiovascular Medicine | www.frontiersin.org 2 May 2022 | Volume 9 | Article 856222 Esteve-Pastor et al. Integrated Approach in Atrial Fibrillation that period in Spain, in each participating center, 1 patient (CrCl) 30–50 ml/min, HAS-BLED ≥ 3, amiodarone use, receiving DOACs was included for every 4 patients receiving platelet aggregation inhibitors use, or body weight ≤ 60 kg. VKAs (predefined ratio in the protocol, 1:4 for DOACs and For patients receiving rivaroxaban, criteria for considering VKAs). Each investigator had to include the first 20 consecutive reduced dose were: CrCl 15–49 ml/min; ≥ 2 of the AF patients who met the inclusion and exclusion criteria (first 4 following: age ≥ 75 years, HAS-BLED ≥ 3, amiodarone use, with DOACs and first 16 with VKAs). platelet aggregation inhibitors use, or body weight ≤ 60 kg. Patients with valvular heart disease (rheumatic valve disease, For patients receiving apixaban, criteria for considering moderate-severe valve disease, prosthesis or valve repair surgery), reduced dose were: ≥ 2 of the following: age ≥ 80 years, younger than 18 years old, or with recent hospital admission were creatinine ≥ 1.5 mg/dl, or body weight ≤ 60 kg; CrCl excluded. All subjects provided signed informed consent. The 15–29 ml/min; ≥ 2 of the following: age ≥ 75 years, HAS- study was conducted according to the ethical principles of the BLED ≥ 3, amiodarone use, platelet aggregation inhibitors Declaration of Helsinki and Good Clinical Practice Guidelines use, or diltiazem use. We had no patients taking edoxaban and was approved by the Clinical Research Ethics Committee therapy in our registry. at Hospital Universitario de San Juan (Spain) with the approval • Adherence to the “B component” refers to better AF number 12/220 and by the Spanish Agency of Medicine and symptom management. We used a validated method, i.e., Health Products as a prospective follow-up post-authorization the modified European Heart Rhythm Association (EHRA) study with the approval number SEC-ACO-2012-01. score was used (20). EHRA Class I refers to asymptomatic AF disease; EHRA Class II refers to mild symptoms and Data Collection normal daily activity not affected; EHRA Class III refers Clinical and demographic data for all AF patients were collected to severe symptoms that modified normal daily activity; in a detailed medical history. Blood sample was collected at and EHRA IV refers to disabling symptoms that result in baseline and in each visit, and we collected some variables the discontinuation of normal daily activity. We defined such as glucose, hemoglobin, creatinine, lipid profile, or HbA1c “well-controlled AF symptoms” if patients had EHRA I-II (hemoglobin A1c). We also collected all drug therapy of the classification. patient at baseline. Coagulation status was determined by the • Adherence to the “C component” refers to “Cardiovascular International normalized ratio (INR) values of the 6 months prior risk factor and comorbidity optimization.” We used strict to the study entry. The estimated time spent in the therapeutic criteria for the management of concomitant diseases range (TTR) was assessed by the Rosendaal method. Stroke according to the international guidelines. We considered risk was calculated using the CHADS2 (15) (Congestive heart the following comorbidities and diseases: hypertension, failure, Hypertension, Age ≥ 75 years, Diabetes mellitus, Stroke diabetes mellitus, heart failure (HF), coronary artery or transient ischemic attack [TIA]) and CHA2 DS2 -VASc scores disease (CAD), peripheral artery disease (PAD), and (16) [Congestive heart failure, Hypertension, Age ≥ 75 years, stroke/TIA. For hypertension, we consider optimal Diabetes mellitus, Stroke or transient ischemic attack, Vascular management if blood pressure is < 140/90 mmHg. Optimal disease, Age 65–74 years and Sex category (female)]. Bleeding risk management of diabetes was defined as HbA1c ≤ 7.5%. was calculated using the HAS-BLED score (17) [Hypertension If HBA1 C values were not available, we consider well- (uncontrolled systolic blood pressure > 160 mmHg), Abnormal controlled diabetic patients if fasting glucose levels renal and/or liver function, previous Stroke, Bleeding history or were ≤ 126 mg/dl. For patients with HF, we consider predisposition (anemia), Labile INR (only applies to a VKA user; as optimal management of the disease if treated with not applicable for a non-VKA user), Elderly (age ≥ 65 years), beta-blockers or diuretics or ACEI/ARBs (angiotensin- and concomitant Drugs (antiplatelet or non-steroidal anti- converting enzyme inhibitors/angiotensin receptor inflammatory drugs) and/or alcohol excess]. blockers). Optimal management of HF patients were consiedered if the patients were treated with two of Definitions those drugs. For patients with CAD, PAD, or stroke/TIA, Following the latest clinical guidelines and ABC pathway we considered as well-managed of those entities if definitions (11), the A, B, and C components for this analysis were LDL ≤ 70 mg/dl [as per previous ESC guidelines (21)] and if defined as follows (Supplementary Figure 1): the patients were treated with statins and with ACEI/ARBs. • Adherence to the “A component” was defined as “avoid Following each component individually, we defined the “ABC stroke/high quality of oral anticoagulation.” For VKA users, pathway adherent group” if all components were fulfilled. If this was fulfilled if TTR ≥ 70%. As all our patients not, the AF disease was considered as non-optimally managed were under oral anticoagulation therapy at enrollment, for according to the ABC criteria (non-ABC group). DOAC users we use the definition of Pastori et al. (18); this was the use of appropriate label-adherent dose, as defined Clinical Outcomes following the EHRA practical guide (19). For patients After 3 years of follow-up, we analyzed adverse clinical outcomes receiving dabigatran, criteria for considering reduced dose according to each ABC criterion fulfilled and the “ABC pathway were: age ≥ 80 years; concomitant use of verapamil; ≥ 2 adherent group.” Thromboembolic events were defined as stroke of the following: age 75–79 years, creatinine clearance or transient ischemic attack or peripheral embolism. Bleeding Frontiers in Cardiovascular Medicine | www.frontiersin.org 3 May 2022 | Volume 9 | Article 856222 Esteve-Pastor et al. Integrated Approach in Atrial Fibrillation events were assessed according to the 2005 International Society Atrial Fibrillation Better Care of Thrombosis and Hemostasis criteria (20): fatal bleeding or Components and Atrial Fibrillation Better symptomatic bleeding in a critical anatomical site (intracranial, intraspinal, intraocular, retroperitoneal, intraarticular, pericardial Care Pathway Adherence or intramuscular with compartment syndrome) and/or bleeding Of the whole cohort, 920 (47.1%) patients achieved good control causing a fall in Hb ≥ 20 g/L, or transfusion of ≥ 2 of oral anticoagulation (A criterion fulfilled); 1,791 (91.6%) units of packed red blood cells. We also collected all- patients had good control of arrhythmia symptomatology (B cause mortality, and cardiovascular mortality was defined if criterion fulfilled); and 682 (34.8%) patients had good control it was secondary to a cardiovascular event (acute coronary of cardiovascular risk factors and comorbidities (C criterion syndrome, heart failure, lethal arrhythmia or sudden death, fulfilled). Only 394 (20.2%) patients had good compliance and artery aneurysm rupture or stroke). MACE (major adverse were in the “ABC pathway adherent” group. cardiovascular events) was defined as the composite of ischemic In comparison with the ABC adherent group, patients with stroke, myocardial infarction, and cardiovascular mortality. AF non-ABC adherent had high prevalence of cardiovascular risk Cardiovascular events included fatal and non-fatal stroke, factors such hypertension (83.9% vs. 66.8%; p < 0.001), diabetes TIA, myocardial infarction, coronary revascularization, and mellitus (32.6% vs. 16.5%; p < 0.001), or chronic kidney disease cardiovascular mortality. Clinically significant events included (20.2% vs. 15.7%; p = 0.046). Patients with AF non-adherent to the composite of stroke, major bleeding, all-cause mortality, acute ABC pathway also had a high prevalence of heart disease (50.8% coronary syndrome, and acute heart failure. An external event vs. 36.8%; p < 0.001), coronary artery disease (21.3% vs. 6.1%; assignment committee evaluated all adverse events. p < 0.001), and high CHA2 DS2 -VASc (3.9 ± 1.6 vs. 2.9 ± 1.4; p < 0.001) and HAS-BLED scores (2.1 ± 1.1 vs. 1.6 ± 0.9; p < 0.001). No differences between sex, age and type of AF were Statistical Analysis observed (Table 1). Normal distribution of continuous variables was tested with the Kolmogorov-Smirnov method. Continuous variables are presented using the mean ± standard deviation or median Clinical Outcomes [interquartile range]. Categorical variables are expressed as After a median follow-up of 1,078 days (IQR: 766–1,113), we percentages. For between-group comparisons, we used the analyzed all the adverse events in the “ABC pathway adherent Student’s t-test for continuous variables and chi-square test group” and to the adherence of each criterion. There was a total of for qualitative variables. Cox regression analyses were used to 255 deaths (107 of them were related with cardiovascular causes), determine the associations between adverse events and each 45 strokes, and 136 major bleedings. component fulfilled individually (“A” criterion, “B” criterion, and “C” criterion) and for “ABC pathway adherent group.” “A” Criterion The independent effect of clinical variables on adverse clinical We observed patients with non-adherence to the “A” criterion outcomes was calculated using a Cox proportional hazards had a higher rate of all-cause mortality (5.69%/year vs. regression, including in the multivariate model only those values 4.44%/year; p = 0.043), cardiovascular mortality (2.65%/year vs. with p < 0.15 on univariate analysis. The models included the 1.57%/year; p = 0.008), and cardiovascular events (3.63%/year ABC components, age, sex, hypertension, diabetes, dyslipidemia, vs. 2.73%/year) compared with adherent patients (see Table 2). coronary artery disease, heart failure, peripheral artery disease, Patients with AF non-adherence to the component A had a stroke/TIA, chronic kidney disease, and Charlson Comorbidity high risk of all-cause mortality (log-rank p-value = 0.057) and Index. Differences in event-free survival were examined with log- cardiovascular mortality (log-rank p-value = 0.008) (Figure 1). rank test, and Kaplan–Meier curves were drafted accordingly. On multivariable regression analysis, “A” criterion adherence Statistical significance was defined as p < 0.05. Statistical analyses was independently related with reduced cardiovascular mortality were performed with Stata version 12 (Stata Corporation, College [HR: 0.67, 95%CI (0.45–0.99); p = 0.048] in comparison with Station, TX, United States). non-adherence (see Table 3 and Supplementary Table 1). “B” Criterion RESULTS Poor control of AF symptoms (non-adherence to B component) had higher rate of adverse events: all-cause mortality We enrolled 2,178 patients in FANTASIIA registry; 1,648 (75.6%) (13.79%/year vs. 4.44%/year; p < 0.001), cardiovascular patients were treated with VKA and 530 (24.3%) patients were mortality (8.33%/year vs. 1.67%/year; p < 0.001), MACE treated with DOACs, of which 267 (50.4% of DOAC group) (11.25%/year vs. 2.83%/year; p < 0.001), stroke (3.24%/year patients were treated with dabigatran, 190 (35.8%) patients were vs. 0.73%/year; p < 0.001), or major bleeding (5.03%/year treated with rivaroxaban, and 73 (13.8%) patients were treated vs. 2.84%/year; p = 0.025) compared with patients with well- with apixaban. A total of 1,956 patients (89% of the sample) controlled AF disease, see Table 2. Patients with poor control completed full follow-up. Finally, we had available data from according to the “B” criterion had high risk of stroke (log-rank 1,955 patients (74.4 ± 9.4 years; 43.2% female patients) for all p-value < 0.001), all-cause mortality (log-rank p-value < 0.001), components of the ABC pathway for this analysis. cardiovascular mortality (log-rank p-value < 0.001), MACE Frontiers in Cardiovascular Medicine | www.frontiersin.org 4 May 2022 | Volume 9 | Article 856222 Esteve-Pastor et al. Integrated Approach in Atrial Fibrillation TABLE 1 | Baseline characteristics of patients according to the Atrial fibrillation TABLE 2 | Distribution of adverse events and annual rates according to the Better Care (ABC) pathway adherence. compliance with each criterion and with ABC pathway. Variable ABC-pathway Non-ABC group P-value Compliance Non-compliance P-value adherence group n = 1,561 n; Annual rate n; Annual rate n = 394 (%/year) (%/year) Age 73.1 ± 9.8 73.9 ± 9.4 0.053 Ischemic stroke Sex (female) 168 (42.6) 692 (44.3) 0.561 “A” criterion 20 (0.85%) 25 (0.96%) 0.720 Comorbidities “B” criterion 34 (0.73%) 11 (3.24%) <0.001 Hypertension 263 (66.8) 1310 (83.9) <0.001 “C” criterion 15 (0.88%) 28 (1%) 0.690 Diabetes mellitus 65 (16.5) 509 (32.6) <0.001 “ABC” pathway 7 (0.69%) 38 (0.96%) 0.410 Dyslipidemia 189 (47.9) 830 (53.2) 0.062 All-cause mortality “A” criterion 105 (4.44%) 150 (5.69%) 0.043 Current smoker 22 (5.6) 76 (4.9) 0.598 “B” criterion 207 (4.44%) 48 (13.79%) <0.001 COPD 57 (14.5) 286 (18.3) 0.072 “C” criterion 94 (5.48%) 152 (5.38%) 0.887 PAD 3 (0.8) 116 (7.4) <0.001 “ABC” pathway 43 (4.20%) 212 (5.33%) 0.156 CKD 62 (15.7) 315 (20.2) 0.046 Cardiovascular mortality Excessive alcohol use 11 (2.8) 61 (3.9) 0.293 Charlson’s Index 0.7 ± 0.9 1.3 ± 1.2 <0.001 “A” criterion 37 (1.57%) 70 (2.65%) 0.008 BMI (kg/m2 ) 28.3 ± 4.9 29.1 ± 4.8 0.009 “B” criterion 78 (1.67%) 29 (8.33%) <0.001 Previous heart disease 145 (36.8) 793 (50.8) <0.001 “C” criterion 37 (2.16%) 67 (2.37%) 0.645 Heart failure 91 (23.1) 475 (30.4) 0.004 “ABC” pathway 15 (1.47%) 92 (2.31%) 0.099 Coronary artery disease 24 (6.1) 332 (21.3) <0.001 Acute myocardial infarction LVEF < 45% 41 (10.4) 186 (11.9) 0.385 “A” criterion 25 (1.07%) 28 (1.06%) 0.980 LVEF 60.3 ± 10.6 58.1 ± 11.5 <0.001 “B” criterion 46 (1%) 7 (2.05%) 0.069 Hb(g/dl) 13.8 ± 1.6 13.6 ± 1.7 0.016 “C” criterion 8 (0.47%) 42 (1.51%) <0.001 eGFR 67.7 ± 22.4 65.8 ± 23.1 0.133 “ABC” pathway 6 (0.59%) 47 (1.19%) 0.097 Previous stroke/TIA 16 (4.1) 315 (20.2) <0.001 MACE Previous major bleeding 9 (2.3) 72 (4.6) 0.046 “A” criterion 69 (2.96%) 99 (3.81%) 0.103 Atrial fibrillation “B” criterion 130 (2.83%) 38 (11.25%) <0.001 Paroxysmal AF 116 (29.4) 454 (29.1) 0.959 “C” criterion 50 (2.94%) 112 (4.04%) 0.045 Persistent AF 66 (16.7) 262 (16.8) “ABC” pathway 24 (2.37%) 144 (3.68%) 0.044 Permanent AF 212 (53.8) 845 (54.1) Cardiovascular events Electrical cardioversion 82 (20.8) 272 (17.4) 0.119 “A” criterion 74 (2.73%) 111 (3.63%) 0.043 AF ablation 20 (5.1) 64 (4.1) 0.393 “B” criterion 143 (2.71%) 42 (8.63%) <0.001 Rhythm control 155 (39.3) 592 (37.9) 0.605 “C” criterion 55 (2.73%) 122 (3.74%) 0.041 Rate control 239 (60.7) 969 (62.1) Concomitant treatment “ABC” pathway 27 (2.32%) 158 (3.43%) 0.048 Digoxin 73 (18.5) 283 (18.1) 0.831 Major bleeding Beta-blockers 239 (60.6) 940 (60.2) 0.873 “A” criterion 68 (2.94%) 78 (3.05%) 0.898 Antiarrhythmic agents 102 (25.9) 379 (24.3) 0.525 “B” criterion 129 (2.84%) 17 (5.03%) 0.025 Diuretic 201 (51.1) 921 (59.0) 0.004 “C” criterion 44 (2.61%) 87 (3.17%) 0.263 ACE/ARB inhibitors 260 (65.9) 1138 (72.9) 0.461 “ABC” pathway 30 (2.99%) 116 (3.0%) 0.995 Antiplatelet agents 20 (5.08) 189 (11.9) <0.001 Clinically significant events Anticoagulant therapy <0.001 “A” criterion 182 (8.10%) 231 (9.21%) 0.167 VKA (n = 1469) 257 (65.2) 1224 (78.5) “B” criterion 347 (7.77%) 66 (20.33%) <0.001 NOACs (n = 467) 137 (34.8) 334 (21.4) “C” criterion 137 (8.21%) 254 (9.48%) 0.176 CHADS2 1.6 ± 1.1 2.4 ± 1.2 <0.001 “ABC” pathway 70 (7.04%) 343 (9.05%) 0.055 CHA2 DS2 -VASc 2.9 ± 1.4 3.9 ± 1.6 <0.001 HAS-BLED 1.6 ± 0.9 2.1 ± 1.1 <0.001 MACE, major adverse clinical outcomes: composite of cardiovascular death, ischemic stroke, and myocardial infarction. Clinically significant events: composite COPD, Chronic obstructive pulmonary disease; PAD, peripheral artery disease; of ischemic stroke, major bleeding, all-cause mortality, acute coronary syndrome, CAD, coronary artery disease; CKD, chronic kidney disease; TIA, transitory and acute heart failure. ischemic attack; LVEF, left ventricular ejection fraction; BMI (kg/m2 ), body mass “A” criterion compliance: 920 (47.95%) patients. index; Hb, hemoglobin; ACE, angiotensin-converting enzyme; ARB, angiotensin “B” criterion compliance: 1791 (91.6%) patients. receptor blockers; VKA, vitamin K antagonists; NOACs, non-vitamin K oral “C” criterion compliance: 682 (34.89%) patients. anticoagulants; CHADS2 = Congestive heart failure or left ventricular dysfunction “ABC pathway” compliance: 394 (20.2%) patients. (1); Hypertension (1), Age ≥ 75 (2), Diabetes mellitus (1), prior Stroke/TIA or Bold values are regarding to statistical significance (it means p < 0.05). systemic embolism (2). CHA2 DS2 -VASc = Congestive heart failure or left ventricular dysfunction (1); Hypertension (1), Age ≥ 75 (2) or 65–74 (1), Diabetes mellitus (1), prior Stroke/TIA or systemic embolism (2), Vascular disease (peripheral artery (log-rank p-value < 0.001), or major bleeding (log-rank disease, myocardial infarction, aortic plaque) (1), Sex category (i.e., female sex) (1); p-value = 0.020) (Figure 2). HAS-BLED = Hypertension (1), Abnormal renal and/or liver function (1), prior Stroke (1), Bleeding history or predisposition (1), Labile INR (1), Elderly (1), Drugs or excess On multivariable regression analysis, “B” criterion adherence alcohol (1). was independently related with lower stroke [HR: 0.28, 95%CI Frontiers in Cardiovascular Medicine | www.frontiersin.org 5 May 2022 | Volume 9 | Article 856222 Esteve-Pastor et al. Integrated Approach in Atrial Fibrillation FIGURE 1 | Kaplan–Meier curves for adverse events in A criterion. (A) All-cause mortality (log-rank test: p-value = 0. 057). (B) Cardiovascular mortality (log-rank test: p-value = 0.008). (0.14–0.59); p < 0.001], all-cause mortality [HR: 0.49, 95%CI MACE (3.68%/year vs. 2.37%/year; p = 0.044) and cardiovascular (0.35–0.69); p < 0.001], cardiovascular mortality [HR: 0.39, events (3.43%/year vs. 2.32%/year; p = 0.048) compared with 95%CI (0.25–0.62); p < 0.001], and MACE [HR: 0.41, 95%CI ABC pathway adherent patients. Adherent ABC patients had a (0.28–0.62); p < 0.001] in comparison with non-adherence (see significant reduction in MACE [HR: 0.64, 95%CI (0.42–0.99); Table 3 and Supplementary Tables 2–5). p = 0.042). All adverse events according to the ABC pathway are shown in Table 2. On Kaplan–Meier analysis, patients non- “C” Criterion adherent to the ABC pathway had a high risk of MACE (log-rank Non-adherence to the C-criterion had a high rate of acute p-value = 0.042) (Figure 4). On the multivariable regression myocardial infarction (1.51%/year vs. 0.47%/year; p < 0.001), analysis, there was no statistically significant independent cardiovascular events (3.74%/year vs. 2.73%/year; p = 0.041), or association with adverse events (see Table 3). MACE (4.04%/year vs. 2.94%/year; p = 0.045) compared with adherent patients (Table 2). Kaplan–Meier curves show that non-adherence to DISCUSSION C-criterion had a high risk of myocardial infarction (log- rank p-value < 0.001) and a trend for MACE (log-rank In real-world anticoagulated AF patients from FANTASIIA p-value = 0.059). Patients with good control of comorbidities registry, we observed a lack of adherence to integrated care had a significantly lower risk of myocardial infarction [HR: 0.31, management of AF following ABC pathway. The integrated ABC 95%CI (0.15–0.66); p < 0.001)] (Figure 3). On the multivariable pathway adherent care is associated with a significant reduction regression analysis, there was no independent association in major cardiovascular events during long follow-up, although of good adherence to C criterion and adverse events (see notable baseline differences between patients with and without Supplementary Table 6). ABC-adherent care are present. Control of symptomatology of AF, as assessed by EHRA functional class (B criterion), was Full “Atrial Fibrillation Better Care associated with the most significant adverse event reductions. Pathway Adherence” Only 20.2% of the cohort were adherent to the ABC pathway, Only 394 (20.2%) patients had full adherence to all the ABC highlighting the low adherence to integrated care management. components. Patients of the non-ABC group had a higher rate of These data were consistent with observations from a recent Frontiers in Cardiovascular Medicine | www.frontiersin.org 6 May 2022 | Volume 9 | Article 856222 Esteve-Pastor et al. Integrated Approach in Atrial Fibrillation TABLE 3 | Unadjusted and adjusted hazard ratios for adverse outcomes according to the criteria fulfilled from atrial fibrillation better care (ABC pathway adherent criteria) compared with non-optimally managed ABC group. Number of patients Number of events HR for event Adjusted HR p-value Stroke “A” criteria fulfilled 920 20 0.89 (0.50–1.60); p = 0.700 0.94 (0.52–1.71) 0.847 “B” criteria fulfilled 1791 34 0.23 (0.12–0.45); p < 0.001 0.28 (0.14–0.59) <0.001 “C” criteria fulfilled 682 15 0.88 (0.47–1.65); p = 0.690 1.36 (0.66–2.80) 0.410 “ABC” criteria fulfilled 394 7 0.71 (0.32–1.60); p = 0.410 1.01 (0.43–2.37) 0.924 All-cause mortality “A” criteria fulfilled 920 105 0.78 (0.61–1.0); p = 0.052 0.84 (0.65–1.08) 0.173 “B” criteria fulfilled 1791 207 0.32 (0.24–0.44); p < 0.001 0.49 (0.35–0.69) <0.001 “C” criteria fulfilled 682 94 1.02 (0.53–1.75); p = 0.903 1.27 (0.98–1.64) 0.075 “ABC” criteria fulfilled 394 43 0.79 (0.57–1.10); p = 0.156 1.12 (0.80–1.58) 0.514 Cardiovascular mortality “A” criteria fulfilled 920 37 0.59 (0.40–0.88); p = 0.009 0.67 (0.45–0.99) 0.048 “B” criteria fulfilled 1791 78 0.20 (0.13–0.31); p < 0.001 0.39 (0.25–0.62) < 0.001 “C” criteria fulfilled 682 37 0.91 (0.61–1.32); p = 0.887 1.37 (0.88–2.14) 0.167 “ABC” criteria fulfilled 394 15 0.64 (0.37–1.10); p = 0.099 0.98 (0.56–1.73) 0.950 Acute myocardial infarction “A” criteria fulfilled 920 25 0.99 (0.58–1.70); p = 0.980 1.12 (0.65–1.94) 0.672 “B” criteria fulfilled 1791 46 0.49 (0.22–1.08); p = 0.069 0.82 (0.35–1.91) 0.638 “C” criteria fulfilled 682 8 0.31 (0.15–0.66); p < 0.001 0.53 (0.24–1.18) 0.121 “ABC” criteria fulfilled 394 6 0.49 (0.21–1.16); p = 0.097 0.83 (0.35–1.99) 0.680 MACE “A” criteria fulfilled 920 69 0.78 (0.57–1.05); p = 0.104 0.87 (0.64–1.19) 0.393 “B” criteria fulfilled 1791 130 0.25 (0.18–0.36); p < 0.001 0.41 (0.28–0.62) 0.001 “C” criteria fulfilled 682 50 0.73 (0.52–1.01); p = 0.059 1.08 (0.75–1.56) 0.676 “ABC” criteria fulfilled 394 24 0.64 (0.42–0.99); p = 0.042 0.98 (0.63–1.53) 0.923 Bold values are regarding to statistical significance (it means p < 0.05). systematic review by Romiti et al. (9) and the study by Pastori risks of non-adherence are needed to ensure optimal uptake in AF et al. (22) in the ATHERO-AF study where only 22.4% of patients patients with both therapies, improving patient adherence and were well managed according to the ABC pathway. persistence with treatment (13, 36, 37). According to the “avoid stroke” (i.e., “A” criterion) with In daily clinical practice, physicians often focus on oral adequate oral anticoagulation, only 47% of patients were anticoagulation or adverse events or observable risk factors adherent. To reduce stroke, mortality, and adverse events but tend to forget the patient’s perspective, quality of life, and in AF patients, good anticoagulation with high TTR with symptomatology related with AF (38). Different studies have VKA or correct dose with DOAC is essential (23, 24). The analyzed the influence of AF symptoms on quality of life, with VKAs have been shown to be highly effective for stroke assessment tools to quantify the burden of this disease (39). prevention in AF, reducing the risk of stroke by 64% and However, the relationship between symptoms and adverse events all-cause death by 26% compared with control/placebo (25), is not widely analyzed in real-world patients. but the effectiveness of VKA is dependent on the quality of In our study, we observed good control of AF symptoms anticoagulation control. Good quality anticoagulation (defined with almost 90% of the sample in EHRA I-II status, and we as TTR > 70%) is related with better outcomes during follow- showed the novel finding that the lack of control of symptoms up (26–28). In case of DOACs, those drugs have demonstrated (B criterion) was the strongest component of the ABC pathway similar or higher efficacy in thromboembolic prevention in AF related with adverse events. Such good control of AF symptoms patients with fixed dose and in the absence of drug monitoring was independently related with a significant reduction in stroke, (29–32). However, nearly one-third of patients may receive all-cause mortality, cardiovascular mortality, and MACE. These an inappropriate dose of DOAC in daily clinical practice, results were slightly different from the results of ORBIT-AF according to EHRA recommendations (33), increasing both registry (40) where there was lower quality of life and higher rates thromboembolic and bleeding risks (34). Hence, management of hospitalization in symptomatic patients (EHRA > 2) but with tools (classical education, smart technology, pill counts. . .) to no difference in mortality rates. improve oral anticoagulation adherence in AF patients involve We also analyzed the influence of risk factors and patients, relatives, and health professionals (physicians, nursery, comorbidities in AF patients according to an integrated pharmacist. . .) (35). Education and counseling to explain the care approach. Risk factor modification, healthy lifestyle, Frontiers in Cardiovascular Medicine | www.frontiersin.org 7 May 2022 | Volume 9 | Article 856222 Esteve-Pastor et al. Integrated Approach in Atrial Fibrillation FIGURE 2 | Kaplan–Meier curves for adverse events in B component. (A) Stroke (log-rank: p-value < 0.001). (B) All-cause mortality (log-rank: p-value < 0.001). (C) Cardiovascular mortality (log-rank: p-value < 0.001). (D) MACE (log-rank: p-value < 0.001). and interventions targeting underlying conditions have to holistic management of AF patients, despite the potential shown a reduction in AF burden and recurrence but with a benefits from adherence to the ABC pathway (9). Stevens et al. multifaceted approach (12). This “C” criterion definition differs (43) recently reviewed 12 clinical studies that focused on the in previous studies, but in the FANTASIIA population, we ABC pathway and observed a wide range in the proportion have selected strict criteria as target control of comorbidities of participants assessed as ABC pathway adherent in the and risk factors according to the current clinical guidelines included studies (7.0–43.8%) and near 37% in ATHERO-AF (Supplementary Figure 1). Hence, only 34.8% of AF patients registry (18). In FANTASIIA registry, there was a reduction in had risk factors and comorbidities under control. Compared MACE/composite outcome in those ABC adherent patients (by with ESC-EHRA EORP Atrial Fibrillation General Long-Term 36%) with similar results compared with ATHERO-AF cohort (AFGen LT) Registry population non-ABC adherent subgroup (18) or post-hoc AFFIRM trial analysis (44). The recent ESC- (41), our patients from FANTASIIA registry were more elderly, EHRA EORP AFGen Long Term registry (41) observed that ABC with a higher prevalence of cardiovascular or other concomitant pathway adherence was associated with a significant lower risk diseases, highlighting the high-risk profile of our real-world for cardiovascular events, CV death, and all-cause death. Also, AF patients. Non-adherence to C criterion had a higher risk, in our registry, we observed that the ABC pathway adherent especially for cardiovascular outcomes (MACE, cardiovascular patients had less cardiovascular events, MACE, and clinically events, and acute myocardial infarction), compared with significant events (that includes mortality) but no difference in adherent patients. LaMori et al. (42) analyzed the comorbidity all-cause mortality rates probably related to the small sample sizes burden of AF patients and observed that almost all (98%) of of the subgroups. the population had at least one additional comorbidity, 90% Compliance with AF management plans, including advice had cardiovascular comorbidities, and ≥ 63% of AF patients on risk factors and lifestyle changes, simplifying assistance had four or more comorbidities in addition to AF, so the high process and prescriptions, better patient education, nurse-led multimorbidity disease burden carried beyond AF status. Indeed, interventions, and close health support, may have a major impact Fauchier et al. (2) analyzed the causes of death in AF patients and on the burden of AF, improving decision-making, quality of life, only 7% were related with stroke accounting for the majority of and outcomes in AF patients (11, 45). Our study is one of the deaths related with a cardiovascular cause(s). few based on a prospective cohort and provides more evidence In the FANTASIIA registry, only 20% of the AF population for the use of ABC pathway as the integrated management of were ABC pathway adherent, highlighting the lack of adherence AF patients (both under VKA and DOAC), also highlighting Frontiers in Cardiovascular Medicine | www.frontiersin.org 8 May 2022 | Volume 9 | Article 856222 Esteve-Pastor et al. Integrated Approach in Atrial Fibrillation FIGURE 3 | Kaplan–Meier curves for adverse events in C criterion. (A) Acute myocardial infarction (log-rank: p-value = 0.001). (B) MACE (log-rank: p-value = 0.059). the importance of the symptom management. Involving patients, ABC pathway during the follow-up and the influence on relatives, and multidisciplinary health professionals in the outcomes are uncertain. Moreover, related with the predefined decision-making process is crucial to facilitate truly integrated or ratio in the protocol, 1:4 for DOACs and VKAs, we could holistic management of AF. not perform individual analysis to validate ABC pathway for DOAC vs. VKA or for each DOAC due to the small sample Strengths and Limitations size, which is a limitation in the generalizability of the results The limitations of the study are derived from its observational in the DOAC group. nature, as inclusion bias could not be completely eliminated, Regarding the difference between adherence to “A criterion” although it was minimized by the criterion of consecutive according to VKA or DOAC therapy, for VKA therapy enrollment. However, differences in baseline risk factors the definition of good adherence according to TTR 70% is characteristics were observed. Unfortunately, we cannot perform fully accepted in the original definition. However, regarding a direct comparison using propensity score matching to DOAC definition, there was no uniform approach in previous homogenize the baseline characteristics due to the sample size, manuscripts. The most correct definition perhaps will be the so this should be considered a limitation of our study. assessment of taking DOAC therapy with pharmacy dispensing Other limitation was related to our use of the robust data from electronic health records, pill count, or laboratory definition for ABC adherence leading to modest sample sizes control of DOACs. No studies have previously validated ABC of each subgroup with low adverse events and lack of statistical pathway in this way in the DOAC group. However, FANTASIIA significance for comparison of outcomes, hence limiting the registry involves 50 centers in Spain, with different electronic and generalizability of the results. Although we have a large follow- non-electronic pharmacy dispensing data, and it is not indicated up of AF patients, the ABC pathway compliance was calculated as the laboratory control of DOAC to assess compliance. For that at baseline, and the variation of different components of the reason, we considered the correct dose of DOAC as an indirect Frontiers in Cardiovascular Medicine | www.frontiersin.org 9 May 2022 | Volume 9 | Article 856222 Esteve-Pastor et al. Integrated Approach in Atrial Fibrillation FIGURE 4 | Kaplan–Meier curves for adverse events in the ABC pathway adherent group. (A) MACE (log-rank: p-value = 0.042). (B) Clinically significant event (log-rank: p-value = 0.053). indicator of correct adherence to A criteria, which is a small ETHICS STATEMENT limitation in the DOAC group of ABC- pathway. Otherwise, there are several strengths in the FANTASIIA The studies involving human participants were reviewed registry, which is a cohort study with prospective long follow-up and approved by the Clinical Research Ethics Committee including a large number of patients with few losses to follow-up, at Hospital Universitario de San Juan (Spain) with the and ≥90% of patients had follow-up data. approval number 12/220 and by the Spanish Agency of Medicine and Health Products as a prospective follow-up post-authorization study with the approval CONCLUSION number SEC-ACO-2012-01. The patients/participants provided their written informed consent to participate in In real-world anticoagulated AF patients from FANTASIIA this study. registry, we observed a lack of adherence to integrated care management of AF following the ABC pathway. AF managed according to the ABC pathway was associated with a significant reduction in adverse outcomes during long follow- AUTHOR CONTRIBUTIONS up, suggesting the benefit of a holistic and integrated approach to AF management. ME-P and FM drafted the manuscript and writing–review and editing-lead. JM and DO performed the statistical analysis. MA, VB-M, and FM performed as conceptualization-lead, DATA AVAILABILITY STATEMENT methodology-lead, and writing-review and editing-lead. GL performed the writing–review and editing-supporting. All The raw data supporting the conclusions of this article will be authors made substantial contributions to the concept and design made available by the authors, without undue reservation. of the work, participated in the acquisition and interpretation of Frontiers in Cardiovascular Medicine | www.frontiersin.org 10 May 2022 | Volume 9 | Article 856222 Esteve-Pastor et al. Integrated Approach in Atrial Fibrillation data, revised the manuscript for important intellectual content, and RD12/0042/0063). The authors are supported by approved the final version of the manuscript, and are able to take RD12/0042/0049 (RETICS) from ISCIII, PI13/00513/FEDER public responsibility for the full text of the article. from ISCIII, Fundación Séneca (19245/PI/14), and Instituto Murciano de Investigación Biosanitaria (IMIB16/AP/01/06). FUNDING SUPPLEMENTARY MATERIAL This study received funding from an unconditional grant from Pfizer/Bristol-Myers Squibb and grants from the The Supplementary Material for this article can be found Instituto de Salud Carlos III (Madrid)-FEDER (RD16/11/00420, online at: https://www.frontiersin.org/articles/10.3389/fcvm. RD12/0042/0068, RD12/0042/0010, RD12/0042/0069, 2022.856222/full#supplementary-material REFERENCES the national registry of atrial fibrillation. JAMA. (2001) 285:2864–70. doi: 10.1001/jama.285.22.2864 1. Burdett P, Lip GYH. Atrial fibrillation in the United Kingdom: predicting 16. Lip GYH, Nieuwlaat R, Pisters R, Lane DA, Crijns HJGM. Refining clinical risk costs of an emerging epidemic recognising and forecasting the cost drivers of stratification for predicting stroke and thromboembolism in atrial fibrillation atrial fibrillation-related costs. Eur Heart J Qual Care Clin Outcomes. 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A subanalysis of the FANTASIIA Registry. Europace. (2018) 20:1577–83. doi: 10.1093/europace/ Conflict of Interest: DO is employed by ODDS, SL. eux316 35. Pritchett RV, Bem D, Turner GM, Thomas GN, Clarke JL, Fellows R, et al. The remaining authors declare that the research was conducted in the absence of Improving the prescription of oral anticoagulants in atrial fibrillation: a any commercial or financial relationships that could be construed as a potential systematic review. Thromb Haemost. (2019) 119:294–307. doi: 10.1055/s- conflict of interest. 0038-1676835 36. Clarkesmith DE, Pattison HM, Lip GYH, Lane DA. Educational intervention Publisher’s Note: All claims expressed in this article are solely those of the authors improves anticoagulation control in atrial fibrillation patients: the TREAT and do not necessarily represent those of their affiliated organizations, or those of randomised trial. PLoS One. (2013) 8:e74037. doi: 10.1371/journal.pone. the publisher, the editors and the reviewers. Any product that may be evaluated in 0074037 this article, or claim that may be made by its manufacturer, is not guaranteed or 37. Clarkesmith DE, Lip GYH, Lane DA. Patients’ experiences of atrial fibrillation endorsed by the publisher. and non-vitamin K antagonist oral anticoagulants (NOACs), and their educational needs: A qualitative study. Thromb Res. (2017) 153:19–27. doi: Copyright © 2022 Esteve-Pastor, Ruiz-Ortiz, Muñiz, Roldán-Rabadán, Otero, 10.1016/j.thromres.2017.03.002 Cequier, Bertomeu-Martínez, Badimón, Anguita, Lip and Marín. This is an open- 38. Wynn GJ, Todd DM, Webber M, Bonnett L, McShane J, Kirchhof P, et al. access article distributed under the terms of the Creative Commons Attribution The European Heart Rhythm Association symptom classification for atrial License (CC BY). The use, distribution or reproduction in other forums is permitted, fibrillation: validation and improvement through a simple modification. provided the original author(s) and the copyright owner(s) are credited and that the Europace. (2014) 16:965–72. doi: 10.1093/europace/eut395 original publication in this journal is cited, in accordance with accepted academic 39. Witassek F, Springer A, Adam L, Aeschbacher S, Beer JH, Blum S, et al. Health- practice. No use, distribution or reproduction is permitted which does not comply related quality of life in patients with atrial fibrillation: the role of symptoms, with these terms. Frontiers in Cardiovascular Medicine | www.frontiersin.org 12 May 2022 | Volume 9 | Article 856222