Nonvalvular atrial fibrillation (NVAF) is a common arrhythmia whose incidence and prevalence increase notably with age. In the adult population of Spain, it has an estimated prevalence of 4.4% (OFRECE study).1 Atrial fibrillation (AF) is not a benign arrhythmia, as morbidity and mortality are significantly increased in patients with this condition, particularly in terms of stroke and other systemic thromboembolic phenomena.2 Fortunately, this risk is considerably lowered by the use of oral anticoagulants, such as the classic vitamin K antagonists (VKAs).3 The last few years have witnessed the development of new direct oral anticoagulants (DOACs) (dabigatran, rivaroxaban, apixaban, and edoxaban) that limit these problems. Clinical trials comparing these drugs with warfarin in patients with NVAF have reported similar or superior efficacy in preventing stroke, with lower rates of severe bleeding, particularly intracranial bleeding, indicating greater safety.4–7 In addition, several meta-analyses have shown that DOACs can decrease mortality in NVAF patients.8 Based on these findings, clinical practice guidelines9,10 recommend these drugs as the anticoagulants of choice for NVAF patients with no contraindications, preferring them over VKAs. Various observational registries and studies using data from insurance companies in the United States have confirmed the safety and effectiveness of DOACs in real-world NVAF patients, with generally favorable results for DOACs vs VKAs.11–16

However, these studies have some methodological limitations and most of them compare DOACs with warfarin sodium, which is not the VKA commonly used in Spain. Furthermore, at the time the present study was designed and initiated, there were no real-world studies in Spain comparing these drugs. The aim of this prospective, observational, multicenter study was to compare the effectiveness and safety of DOACs vs VKAs (mainly acenocoumarol) in real-world patients with NVAF in Spain.

The FANTASIIA study (atrial fibrillation: influence of the level and type of anticoagulation on the incidence of stroke and bleeding events) was designed and developed by the Research Agency of the Spanish Society of Cardiology, with the main objective stated above. The secondary aims were to analyze the quality of VKA anticoagulation and study the characteristics and clinical care related to NVAF in Spain. The study was approved by the Clinical Research Ethics Committee of San Juan Hospital in Alicante and met the requirements and standards of the Declaration of Helsinki and its subsequent amendments for research studies in humans, as well as the current data protection regulations in Spain. It is a nationwide, multicenter, observational study with a prospective follow-up, including consecutive NVAF patients who had been taking oral anticoagulants (DOACs or VKAs) on a stable basis for at least 6 months before enrollment and had provided informed consent for participation.

In addition to the advantages of DOACs related to their pharmacokinetic and pharmacodynamic properties (eg, fixed anticoagulant action, systemic monitoring of anticoagulation is not needed, and few interactions with other drugs, and foods), clinical trials investigating the 4 currently available DOACs4–7 and recently published real-world studies11–15 have reported efficacy similar to or higher than warfarin for stroke prevention, and greater safety in terms of severe bleeding events, in particular intracranial bleeding.4–7 Furthermore, a meta-analysis has even reported a reduction in mortality.8 Based on these results, certain clinical practice guidelines9,10 recommend DOACs as the anticoagulant agents of choice in patients with NVAF, preferring them over VKAs.

Nonetheless, the introduction of DOACs in Spain has been very slow, and the usage rates are much lower than those of neighboring countries.17 This situation is due to several factors. Among the most important may be the restrictions on DOAC prescription imposed by the therapeutic positioning report and the need to authorize its use by the autonomous communities.17 There are other possible reasons for this low utilization, such as poor control of the quality of VKA anticoagulation by physicians,18,19 and the absence of data from Spanish studies confirming the reproducibility of DOAC results in Spain. Several national studies have reported that anticoagulation is poor in around 50% of NVAF patients receiving VKAs, as they were found to be within the therapeutic range in the previous 6 months for less than 60% to 65% of the time,18,19 which is one of the allowed indications for switching to DOACs.17

Until the development of FANTASIIA, there were no multicenter studies comparing the overall effect of DOACs vs VKAs in clinical practice in Spain. Furthermore, the VKA most commonly prescribed in this country is not warfarin (the comparator used in all studies from other countries), which has important pharmacokinetic differences with respect to acenocoumarol (the VKA usually used in Spain). Hence, doubts may arise as to whether the results of these studies can be extrapolated to a setting such as Spain, where the most commonly used anticoagulant is acenocoumarol. FANTASIIA was specifically designed to provide a response to these uncertainties. The results of this study in NVAF patients (Figure 1, Figure 2, Table 2, Table 3) indicate a trend to greater effectiveness and safety of DOACs as a group compared with acenocoumarol in clinical practice in Spain. Patients receiving DOACs at the start of the study showed a statistically significant reduction in all the outcome events (stroke, systemic embolism, major bleeding, cardiovascular death, and all-cause death). Furthermore these reductions were of considerable magnitude in the unadjusted analysis, ranging from 32% for all-cause mortality to 62% for stroke (Table 3).

As could be expected,15 although this was a prospective study, its observational nature and setting of daily clinical practice led to differences in the baseline characteristics of the 2 patient groups (Table 1) that could have impacted the results. In patients receiving DOACs, there was a lower percentage of heart failure, coronary disease, and renal failure, and a higher percentage of previous stroke and major bleeding than in the VKA group. The embolic and hemorrhagic risk profile based on the HAS-BLED and CHA2DS2-VASc scores was, however, similar in the 2 groups, as well as the age, percentage of women, and treatments they were receiving (Table 1). After adjustment for potential confounding factors, a numerically important reduction in the incidence of all events was seen in favor of DOACs (reductions from 14% in mortality to 58% in stroke relative to VKAs) (Table 3).

As is the case of all studies performed in clinical practice,15 FANTASIIA has strengths and limitations. It is a cohort study with prospective follow-up and sample calculation based on the expected incidence of events in both treatment groups, which closely approached the actual results (at 3 years, 21% vs the expected 18% in the VKA group and 15.4% vs the expected 13.5% in the DOAC group). Furthermore, 91% of patients in the VKA group were taking acenocoumarol, which makes the findings applicable to patients in Spain. Last, VKA:DOAC sampling was at a 4:1 ratio to simulate the relative use of the 2 drug classes in Spain, where DOACs accounted for only 20% to 25% of the total of anticoagulants prescribed at the start of the study. FANTASIIA included a large number of patients (2178), there were few losses to follow-up, and more than 90% of patients had follow-up data. The limitations of the study are derived from its observational nature, as inclusion bias could not be completely eliminated, although it was minimized by the criterion of consecutive enrollment. Likewise, there were baseline differences between the groups, with a higher prevalence of previous heart disease and renal failure in the VKA group and stroke and bleeding in the DOAC group, which could have had (and in fact, did have) an influence on the difference in outcomes. In effect, the unadjusted analysis showed highly significant reductions in all outcome events in the DOAC group (Figure 1 and Figure 2), which decreased after adjustment for potential confounding factors. Nonetheless, a trend to a reduction in all outcome measures, both individual and combined, was maintained, with considerable numerical differences in favor of DOACs. Finally, the 4:1 allocation may have produced a certain over-representation or under-representation of patients, depending on the autonomous community where they were enrolled.

Another factor to consider when interpreting the results is the treatment changes during follow-up, which are known to occur in all studies with a lengthy follow-up.14,15 This is particularly true in observational studies, although it has also been seen in clinical trials (exemplified by the discussions regarding the recent CABANA AF ablation study results).20 At the start of the present study, 75.5% of patients were taking VKAs and 24.5%, DOACs. At the end of follow-up, 51.3% were receiving VKAs, 44.1% DOACs, and 4.6% no anticoagulant therapy. The analysis of outcome events was carried out according to the patients’ treatment group at the initial visit, but some events may have taken place while patients were receiving a different treatment from the initial one. This can occur in all observational studies performed in clinical practice and it does not affect the validity of the results. The analysis presented is conservative in the light of the treatment changes, as switches in the treatment group during follow-up (which occurred, although in a small percentage) tend to dilute the magnitude of an effect of treatment, if there is one. The data found are similar to those reported in studies performed in the United States, using information from insurance companies’ databases,11–13 which include a large number of patients but have considerable limitations, and data from European registries,14,15 which are more methodologically robust.

From the clinical perspective, the findings of this study, in which the comparator drug was acenocoumarol, support the applicability to Spain of the results of trials and clinical practice studies performed in other countries. Despite the aforementioned limitations inherent to observational studies, the results indicate that compared with VKA therapy, DOAC use is associated with trends to a lower incidence of major AF-related events, including death, in NVAF patients in Spain. Hence, DOAC use should be increased in Spain to the levels seen in our neighboring countries to improve the prognosis of patients with this condition.20

This study was funded by an unconditional grant from the Bristol-Myers-Squibb and Pfizer Alliance, Spain.

M. Anguita has received fees for lectures and consultancies from Pfizer, Bristol-Myers-Squibb, Daichii-Sankyo and Bayer. M. Ruiz has received fees for lectures and assistance to attend conferences held by Bayer, Boehringer-Ingelheim and Daiichi-Sankyo, and grants from Pfizer-Bristol and Instituto Carlos III. Á. Cequier has received fees for lectures and grants from Abbot, Biosense, Boston, Medtronic, Cordis, Biomens, Orbus Neich and the Spanish Society of Cardiology, and fees for lectures from Astra-Zeneca, Amgen, Bayer, Biotronik, Boehringer-Ingelheim and Daiichi-Sankyo, Ferrer, Sanofi, and Terumo. J. Muñiz has received fees for studies from the Spanish Society of Cardiology and for statistical analyses from Astellas Pharma. L. Badimón Maestro has received fees for lectures from Bayer and Pfizer, and grants from Astra-Zeneca. F. Marín has received fees for lectures and consultancies from Boehringer-Ingelheim, Daiichi-Sankyo and AF-NET, assistance for attending meetings held by Daichii-Sankyo, and grants from Pfizer-BMS and the Spanish Society of Cardiology.