The use and adherence of oral anticoagulants in Primary Healthcare in Catalunya: a real-world data cohort study

Background The use of direct oral anticoagulants (DOAC) for stroke prevention in non-valvular atrial fibrillation (NVAF) has not been previously assessed in our setting. We aimed to describe sociodemographic, comorbidities, co-medication and risk of thromboembolic events and bleeding in patients with NVAF initiating oral anticoagulants (OAC) for stroke prevention, and to estimate adherence and persistence to OAC. Methods Population-based cohort study including all NVAF adult patients initiating OAC for stroke prevention in August 2013-December 2015. Persistence was measured in patients initiating OAC in August 2013-December 2014. Data source is SIDIAP, which captures electronic health records from Primary Health Care in the Catalan Health Institute, covering approximately 5.8 million people. Results 51,690 NVAF patients initiated OAC; 47,197 (91.3%) were naive to OAC and 32,404 initiated acenocoumarol (62.7%). Mean age was 72.8 years (SD 12.3) and 49.4% were women. Platelet-aggregation inhibitors were taken by 9,105 (17.6%) of the patients. 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%)]. Adherence was estimated for patients initiating DOAC and 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

The use and adherence of oral anticoagulants in Primary Healthcare in Catalunya: a realworld data cohort study CURRENT [1][2][3][4].
The level of utilization of the different DOAC in stroke prevention in NVAF has shown to be different among countries, and several cohort studies have shown dissimilar results on effectiveness and safety of these drugs [5][6][7][8][9][10][11][12]. Adequate levels of adherence and persistence to anticoagulant treatment have shown to decrease the occurrence of embolic events [13][14][15][16], so other studies have assessed adherence and persistence to oral anticoagulants (OAC), also showing different results among them [17][18][19][20][21][22][23]. Adherence has been defined as the extent to which the patient conforms to the medication use recommendations specified by the prescriber (frequency of administration, dosage, etc.), and it is divided in three phases: initiation, implementation and persistence [24]. Initiation can be estimated by the prescriptions actually dispensed, implementation can be measured by medication possession ratio (MPR), and persistence is defined as the continuation of the treatment over time [25].    Although the measure of persistence for VKA should be different to the measure for DOAC, in Fig. 2 we show data for both groups of anticoagulants in order to compare them. This figure shows Kaplan-Meier curves for treatment discontinuation of DOAC and VKA in naive patients; there were high DOAC discontinuation rates at treatment start and, over time apixaban showed lower discontinuation rates.

Discussion
We included 51,690 new users of OAC in this population-based cohort study, 41,146 of them had dispensing data available in SIDIAP (79.6%). Approximately 20% of them patients initiated DOAC, pointing out that VKA are still the first therapeutic option for anticoagulation in NVAF in our setting, as recommended by AEMPS. [26] Most patients (83.9%) had CHA 2 DS 2 VASc score ≥ 2, which is the criterion to anticoagulate in NVAF patients according to guidelines [32,33]. Patients with highest risks of stroke were those in the groups of acenocoumarol and apixaban, as shown in previous studies [14,22,34].
Therapeutic adherences at implementation and persistence to OAC were assessed in those patients who were adherent at initiation and started anticoagulation treatment before 2015. Only one third of naive patients received DOAC treatment during at least one year of follow-up, for VKA the proportion was higher. Between them, rivaroxaban group showed the highest percentage of patients with good adherence at implementation (MPR ≥ 80) and dabigatran the lowest. Similar results were also found by Forslund et al. [22] or by Beyer-Westendorf et al. [23] although this last study only analysed rivaroxaban and dabigatran. On the opposite, other studies found higher MPR in apixaban-treated patients [14,35].
Regarding persistence to DOAC in naive patients, apixaban showed higher discontinuation rates during the first month of treatment but at one year, all DOAC showed similar rates. Several studies analysed discontinuation rates at different times during follow-up. After one year, apixaban users were more persistent than other DOAC and VKA users in the studies conducted by Forslund et al. [22] and Johnson et al. [21] Other studies which analysed persistence in naive patients only included dabigatran and rivaroxaban. Rivaroxaban presented better persistence than dabigatran and VKA [23,36].
Manzoor et al. [35] or Martínez et al. [37]  For anticoagulant-experienced patients with more than one year of follow-up in our study, again rivaroxaban showed the largest proportion of patients with good adherence during implementation. Only Manzoor et al. [35] analysed MPR in nonnaive patients and apixaban showed higher MPR in apixaban at 6 months and dabigatran at 9 months. Discontinuation rates in our non-naive patients were much lower than for the naive ones; during the first month since treatment initiation 1.6% apixaban, 4.9% rivaroxaban and 12.6% dabigatran patients discontinued the treatment, and after one year apixaban users showed higher persistence rates than dabigatran and rivaroxaban (66.1% > 64.6% > 48.5%). Manzoor et al. [35] compared persistence between naive and non-naive patients receiving DOAC and the last ones showed higher levels of persistence. Johnson et al. [21] described similar discontinuation rates than for naive patients and at the end-of follow-up patients prescribed apixaban showed improved persistence over dabigatran, rivaroxaban and VKA.
The differences in treatment persistence between naive and anticoagulantexperienced patients in our study could be motivated by a better knowledge of the anticoagulation importance of these patients who previously received mainly VKA, and they were used to attend monthly to PHC centres for INR determination and had optimal levels of drug adherence.
Suboptimal adherence to anticoagulant therapy places patients with AF at risk for stroke or bleeding complications. Our study concludes as most observational studies, that the guidelines recommendations regarding anticoagulant therapy are not routinely followed in clinical practice, and adherence is substantially lower than in clinical trials [3,38].
Some specific limitations in our database are the lack of association between GP's prescriptions and dispensing associated with these prescriptions. This study has missing data from pharmacy claims and for some variables as it is common in observational studies using electronic databases (information bias). The strengths of our study are representativeness for the general population, with a database that covers almost the 80% of the Catalonian population, with complete sociodemographic and health records, long follow-up, and real clinical practice data.  Discontinuation of direct oral anticoagulants and vitamin K antagonists in naive patients