Patients with non-valvular atrial fibrillation (NVAF) have an up to fivefold increased risk of stroke.1 For many years, vitamin K antagonists (VKA) have been the only anticoagulant treatment available. Recently, direct oral anticoagulants (DOACs) have entered the scene, demonstrating a better risk-benefit profile than VKA in randomized controlled trials (RCTs).2–4 Post-marketing real-world observational studies on the effectiveness and safety of dabigatran,5,6 rivaroxaban7 and apixaban8 vs. warfarin have shown general consistency with the respective RCTs. An important advantage of DOACs with respect to AVK is the predictable pharmacokinetics and no need for periodic laboratory monitoring. Thus, the current guidelines of the European Society of Cardiology (ESC) recommend that DOACs should be preferred to VKAs in patients with NVAF who initiate anticoagulation.9,10

Despite its ease of use, DOACs remain high-risk medications which must be handled carefully to avoid bleeding and thrombotic complications. To maximize safety, efficacy, appropriate initial DOAC, dose selection and over time dose adjustments, we must take into consideration patients’ characteristics such as age, renal function, weight, comorbidities and concomitant medications. In addition, careful handling of invasive procedures and surgery should be done, as well as appropriate management of bleeding events. Hence, for proper handling of these drugs, training of physicians attending anticoagulated patients–as well as patient education–is essential.

Nevertheless, the usage rates of DOACs in Spain has been lower than in neighboring countries, mainly because of administrative restrictions limiting the indications of DOACs to situations of poor INR control, ineffectiveness of VKA, contraindications to VKA, increased risk of intracranial hemorrhage or inability to access INR facilities. Moreover, studies evaluating effectiveness and safety of DOAC in the Spanish population are very scarce.11–13 The lack of information about real world practice with DOACs in Spain represents a burden that prevents many patients from getting an adequate treatment of NVAF.

Therefore, we have designed a management program for patients with NVAF initiating DOACs in our health area, in the Hematology Service of the Hospital (in Valencia, Spain). We have included recommendations for indication, dosage, risk factors and influence of renal function, contraindications, and recommendations for switching, management and treatment of all clinical situations that involve DOACs such as bleeding, surgery, monitoring and bibliography, with special focus on the role of the specialists in this field (supplementary guide). Our goal was to evaluate the effectiveness and safety of DOACs in patients initiating anticoagulation for NVAF between 2012 and 2016, reporting the results of our program.

Our center, Hospital Universitario de Sagunto (Valencia, Spain) is a regional hospital that provides care for over 150,000 people and manages over 3500 patients anticoagulated with VKA. In 2012 we designed a management plan for prescription of DOACs patients in patients with NVAF. This study was a longitudinal, prospective observational study in which all patients with NVAF who had signed the informed consent were attending the Hematology Service and they were on treatment with apixaban, rivaroxaban or dabigatran between April, 1st of 2012 and December, 31st of 2016—were included.

According to the management protocol, patients underwent clinical and analytic evaluation before the study began and at three months, one year, two years and three years after initiating DOACs. For each patient, standard clinical data was obtained before the study began, including treatment with platelet aggregation inhibitors. CHA2DS2VASc and HAS-BLED scores.

Following up, we collected analytic data, adverse reactions, thromboembolic events and bleeding events. Clinical effectiveness was assessed according to: the presence or absence of episodes of ischemic stroke, TIA, systemic thromboembolism (TE) and safety—according to major and clinically relevant non-major (NMCR) bleeding (ISTH criteria).14 Appropriate dosing was defined according to international standards included in the Management Program (Supplementary guide).

The confidentiality of records was respected. The study was classified by the Spanish Agency for Medicines and Health Products (EPA-OD) and it was approved by the Research Ethics Committee of the Hospital. The study was conducted under conditions of routine clinical practice and no additional procedures or interventions were performed. All patients gave their informed consent before the study began.

All patients who had completed at least the 3 months visit were included in the analysis. The statistical analyses were performed using the statistical software R, 3.5.2.15 For the descriptive analysis, qualitative variables were described as absolute frequencies and percentages, and quantitative variables were described as median and interquartile range. In order to reduce the possibility of false positive inferences due to multiple comparisons between groups, the p-values were adjusted using the Benjamini & Hochberg method.16 In addition to calculating incidence rates of TE and bleeding events, Kaplan Meier curves were built. The comparison of these curves was performed using the log-rank test. The limit of significance was set at 0.05.

We present the results of a management program for DOACs in a cohort of 445 patients (490 episodes) with NVAF controlled in routine clinical practice with a pre-planned follow-up for up to 3 years, in the Hematology Service at a regional hospital in Spain (Hospital Universitario de Sagunto, Valencia, Spain). There are two main findings in our study, first, despite significant differences in target population between pivotal studies and daily clinical practice, the key messages of the former in terms of the benefit associated with DOACs remain valid. Second, the description of a prevalent pattern of switching between DOACs. In addition, we describe a specific example of implementing international guidelines in form of a consensus program for DOAC management.

The use of DOACs in Spain is markedly lower than in other neighboring countries because reimbursement of prescriptions requires approval by health care authorities. Accordingly, real-world studies evaluating DOACs in the Spanish population are scarce. A few retrospective studies have been published based on databases containing electronic health records17–21 or prospective registries,11 but most of these studies have focused exclusively on the distribution of the different DOACs/doses prescribed and patients characteristics 17–21 and only a few have analyzed stroke and bleeding events.11–13,22 To our knowledge, the study by Cerda et al.,13 performed in a cohort of 1443 patients from a single center is the only one with a comparable methodology to ours, showing basal characteristics and a follow-up similar to those of our cohort of patients. While in Cerda’s study rivaroxaban was the DOAC most commonly prescribed (almost 50% of all the prescriptions), in our study the different DOACs were well balanced.

Of note, the clinical profile of patients in our series differed according to the DOAC administered. These different profiles do not appear to be random but are in line with recent publications analyzing characteristics of patients prescribed with DOAC in routine practice.23,24 There is a higher margin of renal failure and low gastrointestinal bleeding risk of apixaban in the elderly,3 that together with data of the RELY- trial2 it shows a lower risk of ischemic stroke, independent of age. However, an interaction between age and bleeding risk might explain the differences in prescriptions.25

Our population was older and glomerular filtration was worse than in pivotal studies. Median CHADSVASC was also higher, reflecting the fact that real-world patients present more comorbidities than subjects selected in randomized trials. However, our bleeding and thrombotic rates were similar to those in clinical trials. As a whole, patient characteristics in our study differed from pivotal trials, pointing out potential higher risk for clinical complications in our patients. Nevertheless, instead of showing the expected worse outcomes, our results confirm the benefits of DOACs in terms of similar efficacy and lower rates of adverse events compared to acenocoumarol. The contribution of real-world studies is of paramount importance, as shown by previous experiences with other drugs such as ceriva statine in hyperlipidemia, or sibutramine and rimonabant in obesity. In these examples, daily practice did not confirm the safety and efficacy of these drugs postulated in clinical trials. The implications of extending the results of randomized trials to the general population affected by NVAF are far-reaching. A recent publication points out the superiority of all three direct anticoagulants against acenocoumarol in terms of cost-effectiveness in a Spanish setting.26 In the absence of scientific evidence based on clinical or economic data, administrative restrictions for DOACs appear to be unnecessary.

Stroke rates in our study (1.6 events/100 patients-years) were similar to those reported in pivotal trials ranging from 1.1 to 1.7 events/100 patients-years. Similarly, rates of major bleeding (2.4/100 patients-years), NMCR bleeding (5/100 patients-years) and intracranial bleeding (0.5/100 patients-years) in our study were in the range of those reported in randomized trials. Increasing age and previous stroke/TIA were independent predictors of efficacy, in accordance with previous studies.27–32

Although risk factors for bleeding during DOACs therapy have yet to be fully elucidated, and limited data is available on the clinical value of various bleeding risk scores in this setting, the HAS-BLED is the most widely used score with the best evidence for predicting the risk of hemorrhage.10 In our study, increasing age, concurrent aspirin use, and male gender were independent predictors of bleeding. Multiple studies have highlighted the increased propensity of bleeding in elderly patients 7,30,31,33,34 and in those taking the combination of oral anticoagulants plus antiplatelet drugs.35–37,39 The influence of gender on bleeding rates is more controversial, with some studies confirming our own.38–40

Although no head-to-head comparisons between DOACs have been performed, a series of systematic reviews and meta-analysis of RCT and observational studies have compared efficacy and safety of DOACs. In general, compared with warfarin and apixaban offering, DOACs have the most favorable profile.41–43 In our study we did not observe statistically significant differences between specific DOACs.

It is unknown whether all DOACs have similar rates of switching. Information on this matter in the literature is rare, although it is a frequent issue in clinical practice.44 A distinctive feature of our study is that we analyzed DOACs discontinuation, dose adjustments and patterns of crossover between DOACs. A recent meta-analysis in patients with NVAF reviewed studies comparing DOAC-to-DOAC switch prevalence, showing that switching across DOACs is frequent, affecting up to 11% of patients during their life-time.45 Among DOACs, apixaban had lower risk of DOAC-to-DOAC switch compared to dabigatran and rivaroxaban, but no data was available in this study regarding specific causes of switch. Another case series showed a higher cross-over rate with dabigatran.46 These results resembled our own study, where almost 10% of patients underwent dose adjustments or switched to another DOAC, with the highest percentages in dabigatran users (13.6%) and the lowest in patients prescribed apixaban (3.9%). Furthermore, apixaban was the most often chosen DOAC as an alternative option. The lower bleeding rate observed with apixaban treatment in comparison to rivaroxaban and dabigatran in multiple real-world studies23,24,47,48 and its lowest dependence on renal function may influence these treatment decisions.

Concerning evaluation of the appropriateness of dosing, the incidence of off-label use in our study was 23.8%, being underdosing much more common (22%) than over-dosing (1.8%). This numbers are in line with previous studies reporting non-recommended dosing in up to 30% of NVAF patients, the majority due to underdosing.40,49 A bias towards greater concern of bleeding amongst physicians might be a main underlying factor.50 It should be taken into consideration, that in real clinical practice appropriateness cannot always be defined straight-forward. For instance, in our study 36/56 (64%) of patients strictly speaking underdosed with rivaroxaban, were older than 80 years and/or had a creatinine clearance between 50−60 ml/min. Due to the small sample size, we did not analyze differences in outcomes in these cases. Although data in this regard have not been consistent, there are concerns for a potential increase of bleeding or TE events in these cases.40

Finally, it must be highlighted that our program for DOACs management in NVAF patients harmonizes with the recently published guidelines of the ESC which emphasize the importance of implementing an integrated care of AF across all healthcare levels (ABC pathway) to maximize treatment safety and efficacy.9 Although patients on DOACs, unlike those on VKA, need no routine laboratory monitoring, it is essential that anticoagulation clinics get involved and provide guidance surrounding DOACs management. Our program offers a solid and updated reference, spreads knowledge, targets all levels of care and integrates clinical management. In our opinion, centralized follow-up within Hematology Units should be stratified based on patient risk level for TE bleeding complications.

Strengths of our study are first, that clinical and analytic data were collected prospectively, allowing for good data quality, and second, the fact that treatment decisions followed a consensus protocol between acting physicians. The small number of patients, the narrow time of follow-up and the special conditions applying to the Spanish Health Care System are limitations of our study that may reduce the generalization of our conclusions. Another limitation results from the fact that our study could not compare the performance of our program with the previous situation. As a consequence, no statement about potential superiority can be made.

To conclude, our study complements the scant data available on the use of DOACs in NVAF patients in Spain. Confirming a good safety and effectiveness profile, it analyses the pattern of switching between DOACs and it offers a solid model based on consensus protocols under the surveillance of specialized Units.

The authors declare that they have not received funding for conducting this study.

The authors declare that they do not have any conflicts of interest.