Aten Primaria. 2020;52(8):529---538 Atención Primaria www.elsevier.es/ap ORIGINAL ARTICLE The use and adherence of oral anticoagulants in Primary Health Care in Catalunya, Spain: A real-world data cohort study Maria Giner-Sorianoa,b,c , Jordi Cortesd , Ainhoa Gomez-Lumbrerasa,b,e,∗ , Oriol Prat-Vallverdúa,b , Ma Angeles Quijada-Manuittf,g , Rosa Morrosa,b,c,h a Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain b Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Spain c Institut Català de la Salut, Departament de Salut, Generalitat de Catalunya, Barcelona, Spain d Department d’Estadística i Investigació Operativa, Universitat Politècnica de Catalunya, Spain e Departament de Ciències Mèdiques, Facultat de Medicina, Universitat de Girona, Girona, Spain f Department of Clinical Pharmacology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain g Department of Pathology and Experimental Therapeutics, Unitat Docent Campus de Bellvitge, Universitat de Barcelona, L’Hospitalet (Barcelona), Spain h UICEC IDIAP Jordi Gol, Plataforma SCReN, Barcelona, Spain Received 3 March 2020; accepted 21 May 2020 Available online 9 August 2020 KEYWORDS Abstract Atrial fibrillation; Objective: We aimed to describe sociodemographic, comorbidities, co-medication and risk of Oral anticoagulants; thromboembolic events and bleeding in patients with NVAF initiating oral anticoagulants (OAC) Adherence; for stroke prevention, and to estimate adherence and persistence to OAC. Persistence; Setting: Primary Health Care (PHC) in the Catalan Health Institute (ICS), Catalunya, Spain. Electronic health Participants: All NVAF adult patients initiating OAC for stroke prevention in August records 2013---December 2015. Methods: Population-based cohort study. Persistence was measured in patients initiating OAC in August 2013---December 2014. Data source: SIDIAP, which captures electronic health records from PHC in the (ICS), covering approximately 5.8 million people. Results: 51,690 NVAF patients initiated OAC; 47,197 (91.3%) were naive to OAC and 32,404 (62.7%) initiated acenocoumarol. Mean age was 72.8 years (SD 12.3) and 49.4% were women. Platelet-aggregation inhibitors were taken by 9105 (17.6%) of the patients. Persistence and adherence were estimated up to the end of follow-up. For 22,075 patients, persistence was higher among the non-naive patients [n = 258 (61.7%)] than among the naive [n = 11,502 (53.1%)]. ∗ Corresponding author. E-mail address: agomez@idiapjgol.info (A. Gomez-Lumbreras). https://doi.org/10.1016/j.aprim.2020.05.016 0212-6567/© 2020 The Authors. Published by Elsevier España, S.L.U. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). 530 M. Giner-Soriano et al. Adherence was estimated for patients initiating DOAC and it was similar in naive and non-naive patients. Among the naive to DOAC treatment, those starting rivaroxaban showed a highest proportion [(n = 360 (80.1%)] of good adherence at implementation (MPR > 80%) while patients starting dabigatran were less adherent [n = 203 (47.8%)]. Conclusions: Acenocoumarol was the most frequently prescribed OAC as first therapy in NVAF patients. Non-naive to DOAC showed better persistence than naive. Rivaroxaban showed higher proportion of adherent patients during the implementation phase than apixaban and dabigatran the lowest. © 2020 The Authors. Published by Elsevier España, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). PALABRAS CLAVE Uso y adherencia a los anticoagulantes orales en Atención Primaria en Cataluña, Fibrilación auricular; España: estudio de cohortes con datos procedentes de registros electrónicos de salud Tratamiento Resumen anticoagulante oral; Objetivo: Describir datos sociodemográficos, comorbilidades, comedicaciones y riesgo de even- Adherencia; tos tromboembólicos y hemorrágicos de los pacientes con fibrilación auricular no valvular (FANV) Persistencia; que inician tratamiento anticoagulante por vía oral (TAO) para prevención del ictus. Estimar Registros electrónicos adherencia y persistencia al TAO. de salud Emplazamiento: Atención primaria (AP) del Instituto Catalán de Salud (ICS), Cataluña, España. Participantes: Adultos con FANV que inician TAO para prevención de ictus entre agosto del 2013 y diciembre del 2015. Métodos: Estudio de cohortes de base poblacional. Adherencia y persistencia se midieron en pacientes que iniciaban TAO entre agosto del 2013 y diciembre del 2014. Fuente de datos: SIDIAP, base de datos procedentes de registros electrónicos de AP del ICS, que cubre aproximadamente una población de 5,8 millones de personas. Resultados: Cincuenta y un mil seiscientos noventa pacientes con FANV iniciaron TAO, 47.197 (91,3%) eran naïve al TAO y 32.404 (62,7%) iniciaron acenocumarol. Su edad media era 72,8 años (DE 12,3) y el 49,4% eran mujeres; 90105 (17,6%) recibían tratamiento antiagregante plaquetario. Persistencia y adherencia se estimaron hasta el final del seguimiento. La persis- tencia a anticoagulantes orales directos (ACOD) fue mayor en no naïve que en naïve (61,7% vs. 53,1%). La adherencia a ACOD fue similar en los 2 grupos. Entre los naïve, los pacientes que iniciaban rivaroxabán (80,1%) mostraron mayor adherencia en la implementación (MPR > 80%), mientras que los que iniciaban dabigatrán fueron menos adherentes (47,8%). Conclusiones: Acenocumarol fue el anticoagulante más prescrito. Los pacientes no naïve mostraron mejor persistencia al tratamiento que los naïve. Rivaroxabán mostró mayores tasas de adherencia que apixabán y dabigatrán, las menores. © 2020 Los Autores. Publicado por Elsevier España, S.L.U. Este es un artı́culo Open Access bajo la licencia CC BY-NC-ND (http://creativecommons.org/licenses/by-nc-nd/4.0/). Introduction embolic events,13---16 so other studies have assessed adher- ence and persistence to oral anticoagulants (OAC), also Direct oral anticoagulants (DOAC) have been authorised by showing different results among them.17---23 Adherence has the European Medicines Agency for stroke prevention and been defined as the extent to which the patient conforms to systemic embolism in adult patients with non-valvular atrial the medication use recommendations specified by the pre- fibrillation (NVAF) during the last years (in Spain the launch scriber (frequency of administration, dosage, etc.), and it date was 2011 for dabigatran, 2012 for rivaroxaban, 2013 for is divided in three phases: initiation, implementation and apixaban and 2016 for edoxaban). Their efficacy and safety persistence.24 Initiation can be estimated by the prescrip- have been demonstrated in their respective pivotal clinical tions actually dispensed, implementation can be measured trials.1---4 by medication possession ratio (MPR), and persistence is The level of utilisation of the different DOAC in stroke defined as the continuation of the treatment over time.25 prevention in NVAF has shown to be different among Despite the introduction of DOAC for NVAF management, countries, and several cohort studies have shown dissimi- vitamin K antagonists (VKA) are still the first therapeu- lar results on effectiveness and safety of these drugs.5---12 tic option for stroke prevention in Spain, according to the Adequate levels of adherence and persistence to anticoag- Agencia Española de Medicamentos y Productos Sanitarios ulant treatment have shown to decrease the occurrence of (AEMPS).26 Use and adherence of oral anticoagulants in Primary Health Care 531 We have recently described apixaban patients’ charac- dispensing and were analysed by calculating the cumulative teristics according to demographics, comorbidity, risk of percentage of discontinuation (treatment withdrawal or thromboembolic events and comedications in a paper.27 switch) rate. The aim of the present work was to describe the char- Therapeutic adherence during the implementation phase acteristics for all patients initiating any oral anticoagulant was estimated by MPR, which is the ratio between the days drug (DOAC and VKA) for stroke prevention in NVAF and to of treatment covered by the medication dispensed and the estimate adherence during the implementation phase and total number of days between the index date and the last persistence to DOAC treatment. dispensing, and it was measured in persistent patients (those with at least one year of no discontinuation). Values of MPR above 80% were considered as good adherence during imple- Material and methods mentation. The package size has been used to estimate days of supply for DOACs (rivaroxaban once daily, dabigatran and This is an observational population-based cohort study of apixaban twice daily) as the WHO method estimation using adult patients receiving DOAC and VKA for stroke prevention defined daily dose does not separate between standard and in NVAF, identified in the primary healthcare (PHC) database low dose.30 Adherence of VKA treatment cannot be properly SIDIAP (Information System for Research in Primary Care)28 estimated with the same method, as doses are not the same in Catalonia, Spain. The study cohort included all individ- for every day of the week, they change after INR alterations uals diagnosed with NVAF who had a new prescription for and, moreover, warfarin and acenocoumarol pharmaceuti- apixaban, dabigatran, rivaroxaban or VKA (acenocoumarol cal products in Spain are available at different doses and or warfarin) from August 2013 until December 2015. We contain different numbers of tablets. Thus, adherence data excluded from the study those patients with a regis- in this paper are only described for DOAC. tered diagnosis of valvular heart disease, including patients with mitral prosthetic valves. All patients enrolled were subdivided in four groups according to the treatment initi- Statistical analysis ated: apixaban, dabigatran, rivaroxaban and VKA. Patients were considered naive if they did not have prior prescrip- Sociodemographic characteristics for the four groups at tion of any OAC during 12 months before index date, or the start date are provided: (1) for all variables, num- non-naive if they had been previously treated during the ber and percentage of missing data; (2) for categorical previous 12 months with a different OAC from the OAC variables (sex, toxic habits and MEDEA index31 ), num- that caused the entrance to the study cohort. Patients ber and percentage for each category; (3) for continuous were followed-up until the discontinuation of anticoagulant variables (age, body mass index), mean and standard devi- treatment. ation (SD). We report the total number of patients with The data source was SIDIAP,28 which currently collects at least one disease and the number and percentage of anonymized information from 279 primary health care cen- patients with each specific condition for all groups (apix- tres managed by the Catalan health institute (ICS), which aban, dabigatran, rivaroxaban and VKA). Concurrent use of covers more than 5.8 million patients (approximately 80% of medications at the start date was quantified by the num- the Catalonia population, or more than 10% of the Spanish ber and percentage of users. Risk of stroke and major population). The information in SIDIAP is generated from dif- haemorrhage event were assessed at the start date with ferent data sources: (1) ECAPTM (electronic health records CHA2 DS2 VASc32 and HAS-BLED.33 For each score, number and in PHC); which includes information since 2006 on sociode- percentage of each category for the five drugs groups are mographic characteristics, health conditions registered as described. ICD-10 codes,29 General Practitioners’ prescriptions, clini- Monthly discontinuation rates for all anticoagulant during cal parameters and toxic habits. (2) Laboratory data. (3) the first year of treatment were also calculated in order to Pharmacy invoice data available since 2005: information on estimate the persistence. We conducted survival analyses all pharmaceutical products dispensed by community phar- of the time from the index date to the discontinuation date macies with ICS prescriptions, by ATC codes.30 using survival curves drawn using the Kaplan---Meier method. We first described demographics, comorbidity, risk of Censoring was considered at end of follow-up, death or date thromboembolic events and comedications of all patients of treatment discontinuation. For each DOAC group, number with a new prescription of OAC, and secondly, we described and percentage of users with good adherence and summary medication adherence during implementation and persis- statistics for MPR were estimated. tence to anticoagulant treatment for those patients whose Analysis was conducted using SAS software, version 9.4 dispensing data were available and had at least one year (SAS Institute). Detailed methodology for summary and of follow-up in SIDIAP database, during the period between statistical analyses of data collected in this study are doc- August 2013 and December 2014 in order to analyse data of umented in the Statistical Analysis Plan, which is dated, at least one year after initiation. filed and maintained by the sponsor and can be accessed To calculate adherence during implementation and at request to the corresponding author. persistence phases we only took into account those patients who were adherent during initiation, meaning those who had OAC prescribed and dispensed. Persistence was defined Ethics approval as no discontinuation of treatment. Discontinuation rates of OAC were defined by lack of subsequent dispensing of the The study protocol was approved by the Ethics Committee index drugs within 2 months after last supply day of the last of the ‘IDIAPJGol’ and classified by the AEMPS. 532 M. Giner-Soriano et al. MEASURE OF DISPENSING ADHERENCE AND USERS NEW USERS DATA PERSISTENCE 41,146 NVAF patients 100, 320 NVAF 51,690 NVAF patients 22,075 NVAF patients with dispensing patients with a with initiating prescription of a new register of anticoagulant anticoagulants in prescription of anticoagulants in treatment in Aug Aug 2013-Dec 2015 anticoagulants in Aug SIDIAP in Aug 2013- 2013-Dec 2015 2013-Dec 2014 Dec 2015 Apixaban 6,169 Apixaban 6,135 Apixaban 2,549 Apixaban 1,082 (6.1%) (11.8%) (6.2%) (4.9%) Dabigatran 5,485 Dabigatran 3,808 Dabigatran 2,245 Dabigatran 1,255 (5.5%) (7.4%) (5.5%) (5.7%) Rivaroxaban 7,703 Rivaroxaban 6,694 Rivaroxaban 3,361 Rivaroxaban 1,459 (7.7%) (13%) (8.2%) (6.6%) VKA 80,963 (80.7%) VKA 35,053 (67.8%) VKA 32,991 (80.1%) VKA 18,279(82.9) Figure 1 Flowchart of patients included in the study. NVAF: non-valvular atrial fibrillation, VKA: vitamin K antagonists. Results for rivaroxaban (30.6%) and for dabigatran (24.2%). Discontinuation rates in naive patients after one year of We analysed 51,690 NVAF patients with a new OAC pres- treatment were similar between the three DOAC, with cription during the study period; 47,197 (91.3%) were OAC approximately 60% of patients stopping treatment. In all naive patients and 4493 (8.7%) were non-naive, and out of the naive patients the persistence at one year was less than the overall number of patients, 16,637 (32.2%) received a 50% except for the acenocoumarol naive patients in whom it DOAC prescription and 35,053 (67.8%), VKA (Fig. 1, Table 1). was of 56.8%. Persistence was higher in non-naive patients Demographics, risk of stroke and haemorrhage, comorbidi- with an observed persistence of more than 50% at one year, ties and comedications are described in Table 1. Patients being higher for warfarin non-naive patients (77.1%) than initiating anticoagulants had a mean age of 72.8 years (SD for DOAC, where the maximum persistence was observed for 12.3), 49.4%% of them were women and 83.9% of patients apixaban patients (66.1%) and the minimum for the dabiga- had a CHA2 DS2 VASc score ≥2. The youngest patients were tran (48.5%) patients. those initiating warfarin (70.5 years) and the oldest, those For the DOAC naive patients with at least one year of with acenocoumarol (73.5). There was a higher proportion of follow-up (n = 1299, 37.9%, Table 3), the highest adherence patients prescribed with apixaban with a CHA2 DS2 VASc score at implementation was for rivaroxaban (80.1%), followed ≥2 than for the rest of the drugs (86.1%) and the highest by apixaban (61.3%) and dabigatran (47.8%). For DOAC haemorrhagic risk was for acenocoumarol-treated patients non-naive, 225 (60.6%) patients did not discontinue DOAC (40.6% with HAS-BLED ≥3 as compared to 23.1---35.0% treatment during the first year and among them, the largest patients with HAS-BLED ≥3 in patients receiving other OAC). proportion of patients with good adherence was for rivaroxa- The most frequent comorbidities were hypertension (68%), ban (81.7%) and the lowest for dabigatran (34.0%). Although diabetes (31.7%) and cancer (25.6%), and the most fre- the measure of persistence for VKA should be different to the quent comedications were proton pump inhibitors (60.4%), measure for DOAC, in Fig. 2 we show data for both groups of agents acting on the renin---angiotensin system (55.9%) and anticoagulants in order to compare them. This figure shows statins (42.4%). Dispensing data were available for 41,146 Kaplan---Meier curves for treatment discontinuation of DOAC patients (79.6%) of those patients; 8155 (19.9%) patients and VKA in naive patients; there were high DOAC discon- initiated DOAC treatment and 32,991 (80.1%) initiated tinuation rates at treatment start and, over time apixaban VKA (Fig. 1). showed lower discontinuation rates. Adherence at implementation and persistence were assessed through dispensing data for patients who initiated anticoagulant treatment with OAC between August 2013 Discussion and December 2014 (n = 22,075), being only 1.9% of them (n = 418) non-naive patients. Of the 22,075 patients, 3796 We included 51,690 new users of OAC in this population- (17.2%) received DOAC; 3425 (n = 15.8%) of them were naive based cohort study, 41,146 of them had dispensing data and 371 (88.7%) were anticoagulant-experienced patients available in SIDIAP (79.6%). Approximately 80% of the (Table 2). patients initiated VKA rather than DOAC, pointing out that During the first month of treatment, all DOAC-naive VKA are still the first therapeutic option for anticoagulation patients presented high discontinuation rates, being the in NVAF in our setting, as recommended by AEMPS.26 Most discontinuation rates higher for apixaban (33.1%) than patients (83.9%) had CHA2 DS2 VASc score ≥2, which is the Use and adherence of oral anticoagulants in Primary Health Care Table 1 Baseline characteristics of patients with new prescriptions of anticoagulants. N, % Total Apixaban Dabigatran Rivaroxaban Acenocoumarol Warfarin (n = 51,690) (n = 6135) (n = 3808) (n = 6694) (n = 32,404) (n = 2649) Naive patients 47,197 (91.3%) 4712 (76.8%) 2855 (75.0%) 5132 (76.7%) 32,212 (99.4%) 2286 (86.3%) Non-naive patients 4493 (8.7%) 1423 (23.2%) 953 (25.0%) 1562 (23.3%) 192 (0.6%) 363 (13.7%) Female 25,559 (49.4%) 3412 (55.6%) 1878 (49.3%) 3460 (51.7%) 15,625 (48.2%) 1184 (44.7%) Mean age, years (SD) 72.8 (12.3) 73.2 (11.0) 71.6 (12.0) 71.0 (12.9) 73.5 (12.3) 70.5 (13.5) ≥80 years-old 17,200 (33.3%) 1879 (30.6%) 1065 (28.0%) 1809 (27.0%) 11,737 (36.2%) 710 (26.8%) Smoking habit 11,701 (22.6%) 1313 (21.4%) 826 (21.7%) 1483 (22.2%) 7302 (22.5%) 777 (29.3%) Glomerular filtration rate (mL/min/1.73 m2 ) Missing GFR 9788 (18.9%) 1249 (20.4%) 839 (22.0%) 1636 (24.4%) 5561 (17.2%) 503 (19.0%) GFR ≥ 60 30,687 (59.4%) 3605 (58.8%) 2363 (62.1%) 3908 (58.4%) 19,248 (59.4%) 1563 (59.0%) GFR 30---45 10,248 (19.8%) 1198 (19.5%) 577 (15.1%) 1088 (16.3%) 6867 (21.1%) 518 (19.6%) GFR < 30 967 (1.9%) 83 (1.4%) 29 (0.8%) 62 (0.9%) 728 (2.2%) 65 (2.5%) BMI groups (kg/m2 ) Missing 12,408 (24.0%) 1685 (27.5%) 1138 (29.9%) 2057 (30.7%) 6932 (21.4%) 596 (22.5%) 18.5---25 (normal) 6701 (13.0%) 676 (11.0%) 416 (10.9%) 735 (11.0%) 4501 (13.9%) 373 (14.1%) <18.5 (underweight) 201 (0.4%) 18 (0.3%) 18 (0.5%) 16 (0.2%) 141 (0.4%) 8 (0.3%) 25---30 (overweight) 15,507 (30.0%) 1722 (28.1%) 1041 (27.3%) 1771 (26.5%) 10,142 (31.3%) 831 (31.4%) >30 (obese) 16,873 (32.6%) 2034 (33.2%) 1195 (31.4%) 2115 (31.6%) 10,688 (33.0%) 841 (31.7%) CHA2 DS2 VASc 0 or 1 (woman) 4902 (9.5%) 480 (7.8%) 476 (12.5%) 887 (13.3%) 2738 (8.4%) 321 (12.1%) 1 3398 (6.6%) 375 (6.1%) 280 (7.4%) 500 (7.5%) 2040 (6.3%) 203 (7.7%) ≥2 43,390 (83.9%) 5280 (86.1%) 3052 (80.1%) 5307 (79.2%) 27,626 (85.3%) 2125 (80.2%) HAS-BLED 0 4166 (8.1%) 540 (8.8%) 509 (13.4%) 903 (13.5%) 1918 (5.9%) 296 (11.2%) 1---2 29,391 (56.9%) 3927 (64.0%) 2405 (63.2%) 4243 (63.4%) 17,322 (53.5%) 1494 (56.4%) ≥3 18,133 (35.0%) 1668 (27.2%) 894 (23.4%) 1548 (23.1%) 13,164 (40.6%) 859 (32.4%) Comorbidities Heart failure 6133 (11.9%) 866 (14.1%) 439 (11.5%) 783 (11.7%) 3656 (11.3%) 389 (14.7%) Peripheral artery disease 2764 (5.3%) 323 (5.3%) 154 (4.0%) 294 (4.4%) 1801 (5.6%) 192 (7.2%) Ischaemic heart disease 7406 (14.3%) 802 (13.1%) 472 (12.4%) 856 (12.8%) 4795 (14.8%) 481 (18.2%) Acute myocardial infarction 2460 (4.8%) 246 (4.0%) 130 (3.4%) 263 (3.9%) 1638 (5.1%) 183 (6.9%) Hypertension 35,144 (68.0%) 4295 (70.0%) 2428 (63.8%) 4364 (65.2%) 22,305 (68.8%) 1752 (66.1%) Diabetes mellitus 16,403 (31.7%) 1986 (32.4%) 1146 (30.1%) 1981 (29.6%) 10,425 (32.2%) 865 (32.7%) Cerebrovascular disease 6248 (12.1%) 891 (14.5%) 523 (13.7%) 731 (10.9%) 3725 (11.5%) 378 (14.3%) Cancer 13,211 (25.6%) 1606 (26.2%) 940 (24.7%) 1698 (25.4%) 8249 (25.5%) 718 (27.1%) Comedications Proton pump inhibitors 31,200 (60.4%) 4308 (70.2%) 2346 (61.6%) 4357 (65.1%) 18,489 (57.1%) 1700 (64.2%) Drugs used in diabetes 11,684 (22.6%) 1404 (22.9%) 805 (21.1%) 1348 (20.1%) 7494 (23.1%) 633 (23.9%) Platelet aggregation inhibitors 9105 (17.6%) 985 (16.1%) 518 (13.6%) 997 (14.9%) 6082 (18.8%) 523 (19.7%) Diuretics 19,051 (36.9%) 2131 (34.7%) 1211 (31.8%) 2223 (33.2%) 12,281 (37.9%) 1205 (45.5%) Beta blocking agents 21,113 (40.8%) 2075 (33.8%) 1576 (41.4%) 2374 (35.5%) 13,867 (42.8%) 1221 (46.1%) Calcium channel blockers 10,389 (20.1%) 1197 (19.5%) 735 (19.3%) 1266 (18.9%) 6669 (20.6%) 522 (19.7%) Agents acting on the renin---angiotensin system 28,880 (55.9%) 3469 (56.5%) 2070 (54.4%) 3575 (53.4%) 18,377 (56.7%) 1389 (52.4%) Statins 21,922 (42.4%) 2657 (43.3%) 1522 (40.0%) 2722 (40.7%) 13,714 (42.3%) 1307 (49.3%) Non-steroidal anti-inflammatory drugs 6429 (12.4%) 1805 (29.4%) 623 (16.4%) 1594 (23.8%) 2239 (6.9%) 168 (6.3%) SD: standard deviation, GFR: glomerular filtration rate, BMI: body mass index. 533 534 Table 2 Descriptive of adherence and discontinuation rates of anticoagulants in naive and non-naive patients. First year discontinuation, n (%) Naive patients Total (n = 21,657) Apixaban (n = 958) Dabigatran (n = 1152) Rivaroxaban (n = 1315) Acenocumarol (n = 16,953) Warfarin (n = 1279) No discontinuation 11,502 (53.1%) 375 (39.1%) 425 (36.9%) 499 (37.9%) 9634 (56.8%) 569 (44.5%) Discontinuation at 1st month 1854 (8.6%) 317 (33.1%) 279 (24.2%) 402 (30.6%) 840 (5.0%) 16 (1.3%) Discontinuations at 6th month 6420 (29.6%) 472 (49.3%) 564 (49.0%) 679 (51.6%) 3648 (21.5%) 457 (35.7%) Discontinuations at 1st year 10,155 (46.9%) 583 (60.9%) 727 (63.1%) 816 (62.1%) 6719 (39.6%) 710 (55.5%) Non-naive patients Total (n = 418) Apixaban (n = 124) Dabigatran (n = 103) Rivaroxaban (n = 144) Acenocumarol (n = 12) Warfarin (n = 35) No discontinuation 258 (61.7%) 82 (66.1%) 50 (48.5%) 93 (64.6%) 6 (50.0%) 27 (77.1%) Discontinuation at 1st month 23 (5.5%) 2 (1.6%) 13 (12.6%) 7 (4.9%) 1 (8.3%) 0 (0.0%) Discontinuations at 6th month 99 (23.7%) 19 (15.3%) 39 (37.9%) 33 (22.9%) 5 (41.7%) 3 (8.6%) Discontinuations at 1st year 160 (38.3%) 42 (33.9%) 53 (51.5%) 51 (35.4%) 6 (50.0%) 8 (22.9%) M. Giner-Soriano et al. Use and adherence of oral anticoagulants in Primary Health Care 535 Table 3 Descriptive statistics of adherence rates of direct oral anticoagulants in naive and non-naive patients. Medication possession ratio, n (%) Naive patients (n = 3425) Apixaban (n = 958) Dabigatran (n = 1152) Rivaroxaban (n = 1315) Less than one year of follow-up 583 (60.9%) 727 (63.1%) 816 (62.1%) N with at least 1 year of follow-up 375 (39.1%) 425 (36.9%) 499 (37.9%) Non-adherence (<80%) 145 (38.7%) 222 (52.2%) 139 (27.9%) Good adherence (≥80%) 230 (61.3%) 203 (47.8%) 360 (80.1%) MPR, median (IQR) 90.4 (53.4---98.6) 79.5 (72.3---95.3) 92.6 (77.1---99.7) Non-naive patients (n = 371) Apixaban (n = 124) Dabigatran (n = 103) Rivaroxaban (n = 144) Less than one year of follow-up 42 (33.9%) 53 (51.5%) 51 (35.4%) N with at least 1 year of follow-up 82 (66.1%) 50 (48.5%) 93 (64.6%) Non-adherence (< 80%) 27 (32.9%) 33 (66.0%) 17 (18.3%) Good adherence (≥80%) 55 (67.1%) 17 (34.0%) 76 (81.7%) MPR, median (IQR) 94.5 (53.4---98.6) 75.1 (71.6---94.7) 99.7 (84.4---99.7) MPR: medication possession ratio, IQR: interquartile range. criterion to anticoagulate in NVAF patients according to Therapeutic adherences at implementation and persis- guidelines.34,35 Patients with highest risks of stroke were tence to OAC were assessed in those patients who were those in the groups of acenocoumarol and apixaban, as adherent at initiation and started anticoagulation treat- shown in previous studies for the other VKA, warfarin.14,22,36 ment before 2015. Only one third of naive patients received Naive APIXABAN 1.0 DABIGATRAN RIVAROXABAN ACENOCUMAROL WARFARIN 0.8 0.6 0.4 0.2 0.0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 Years Figure 2 Discontinuation of direct oral anticoagulants and vitamin K antagonists in naive patients. 536 M. Giner-Soriano et al. DOAC treatment during at least one year of follow-up, for data from pharmacy claims and for some variables as it is VKA the proportion was higher. Between them, rivaroxaban common in observational studies using electronic databases group showed the highest percentage of patients with good (information bias). The strengths of our study are repre- adherence at implementation (MPR ≥80) and dabigatran the sentativeness for the general population, with a database lowest. Similar results were also found by Forslund et al.22 that covers almost the 80% of the Catalonian population, or by Beyer-Westendorf et al.23 although this last study only with complete sociodemographic and health records, long analysed rivaroxaban and dabigatran. On the opposite, other follow-up, and real clinical practice data. studies found higher MPR in apixaban-treated patients.14,37 Regarding persistence to DOAC in naive patients, apix- aban showed higher discontinuation rates during the first month of treatment but at one year, all DOAC showed sim- ilar rates. Several studies analysed discontinuation rates at What is known on the topic different times during follow-up. After one year, apixaban users were more persistent than other DOAC and VKA users • The level of utilisation of the different DOAC in in the studies conducted by Forslund et al.22 and Johnson stroke prevention in NVAF has shown to be differ- et al.21 ent among countries, and several cohort studies have Other studies which analysed persistence in naive shown dissimilar results on adherence, effectiveness patients only included dabigatran and rivaroxaban. Rivarox- and safety of these drugs. aban presented better persistence than dabigatran and • Adequate levels of adherence and persistence to VKA.23,38 anticoagulant treatment have shown to decrease the Manzoor et al.37 or Martínez et al.39 studied all DOAC occurrence of embolic events. together as a group. The first one showed higher levels of persistence to DOAC in anticoagulant-experienced patients What this study contributes over time. Martínez et al. found higher levels of persistence in DOAC versus VKA users, which slightly decreased during • Vitamin K antagonists are still the first option to anti- the first year of follow-up (from 94.7% of persistents to DOAC coagulate NVAF patients in our setting. at 3 months to 72.9% at 12 months). • We measured adherence and persistence for DOAC For anticoagulant-experienced patients with more than patients. Adherence was higher for rivaroxaban, fol- one year of follow-up in our study, again rivaroxaban showed lowed by apixaban and dabigatran. the largest proportion of patients with good adherence dur- • Persistence to DOAC was low in our setting, which ing implementation. Only Manzoor et al.37 analysed MPR may result in higher risk of thromboembolic events. in non-naive patients and apixaban showed higher MPR in Discontinuation rates were higher in naive than in apixaban at 6 months and dabigatran at 9 months. Dis- non-naive patients. This may be caused by better continuation rates in our non-naive patients were much knowledge of the importance of treatment adher- lower than for the naive ones; during the first month since ence in patients who have previously received VKA, treatment initiation 1.6% apixaban, 4.9% rivaroxaban and which need a more strict management. 12.6% dabigatran patients discontinued the treatment, and after one year rivaroxaban users showed lower persistence rates (48.5%) than apixaban and dabigatran (66.1% and 64.6%, respectively). Manzoor et al.37 compared persistence between naive and non-naive patients receiving DOAC and Conflict of interest the last ones showed higher levels of persistence. Johnson et al.21 described similar discontinuation rates than for naive The authors declare that they have no conflict of interest. patients and at the end-of follow-up patients prescribed apixaban showed improved persistence over dabigatran, rivaroxaban and VKA. Acknowledgments The differences in treatment persistence between naive and anticoagulant-experienced patients in our study could The authors thank María Aragón and Darío García from SIDIAP be motivated by a better knowledge of the anticoagulation for data management. importance of these patients who previously received mainly VKA, and they were used to attend monthly to PHC cen- tres for INR determination and had optimal levels of drug References adherence. Suboptimal adherence to anticoagulant therapy places 1. Connolly S, Ezekowitz M, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with patients with AF at risk for stroke or bleeding complications. atrial fibrillation. N Engl J Med. 2009;361:1139---51. 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