 neighbouring countries would be more desirable than to further divide regions with the result of precluding meaningful comparisons.
Based on the above considerations, we extracted data on the baseline characteristics of patients from BeNe that were enrolled in ETNA-AF-Europe; determined the proportional use of 30 mg OD and 60 mg OD edoxaban, and whether dose selection was in accordance with the SmPC (except for concomitant use of p‑gp inhibitors). We then compared these findings with those from OEC to assess for clinically important regional differences.
In line with our rationale to interpret findings from continental or global studies in a regional context, we also compared characteristics of patients observed in ETNA-AF-Europe that were from BeNe with those from the corresponding countries once enrolled in the Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48 (ENGAGE-AF-TIMI 48) trial [ 3 ].
A total of 13,639 (97.6% of the 13,980 enrolled patients in ETNA-AF-Europe) were included in our analyses. Of these, 2579 (18.9%) were from BeNe: 1316 (9.6%) from Belgium and 1263 (9.3%) from the Netherlands (Fig. 1). The baseline demographics and clinical characteristics for patients enrolled throughout all OEC, and those in BeNe, stratified by dose of edoxaban, are summarised in Tab. 1.
Overall, 86.4% and 82.4% of patients in BeNe and OEC, respectively, were treated with edoxaban at doses conforming to the SmPC. Relatively fewer patients in BeNe compared to OEC were treated with the reduced dose of edoxaban (14.8% vs 25.4%), but the distribution of 30 mg prescriptions in the absence of any dose reduction criteria was similar in both regions: 36.9% of 30 mg users (5.5% of all patients) in BeNe, compared with 35.5% (9.0% of all patients) in OEC (Fig. 2).
Mean CHA 2DS 2-VASc scores were 2.6 for 60 mg users and 3.6 for 30 mg users in BeNe, compared with 3.0 and 3.8, respectively, in OEC. Mean HAS-BLED scores were 2.3 for patients on standard dose edoxaban and 2.9 for those on the reduced dose in BeNe, compared with 2.5 and 3.0, respectively, in OEC (Fig. 3). Overall, in patients from BeNe, a history of cardiovascular disease was less prevalent than in OEC, in particular hypertension (61.6% vs 80.4%) and diabetes mellitus (17.3% vs 23.1%). In contrast, prior ischaemic events were more often reported in BeNe compared with in OEC.
Physicians from BeNe less often described their patients as frail compared with those from OEC (5.9% versus 11.7%). This trend was prevalent in both dosing groups: in BeNe 19.1% of patients on 30 mg were considered frail, and 3.6% of those on 60 mg, compared with 26.1% and 6.8%, respectively, in OEC.
The current type of AF also differed between the two regions, which was most marked for the 30 mg group. Thus, for BeNe patients prescribed 30 mg of edoxaban, 65.7% had paroxysmal AF and 11.3% permanent AF, compared with 48.1% and 27.7%, respectively, of patients prescribed 30 mg in OEC. For the patients on 60 mg from BeNe, paroxysmal AF was reported in 64.7% of cases and permanent AF in 11.2%, relative to 51.8% and 19.5%, respectively, in the other regions of Europe.
The baseline characteristics of patients from BeNe enrolled in the ETNA-AF-Europe registry and those from the corresponding countries included in the ENGAGE-AF-TIMI 48 trial are summarised in Tab. 2.
Overall, 302 patients from BeNe were enrolled in the RCT (vs 2579 in the registry). CHA 2DS 2-VASc scores were much lower in the registry than in the RCT (mean: 2.8 vs 4.2), as were the rates of prior cardiovascular diseases. Conversely, HAS-BLED scores were higher in ETNA-AF-Europe than in ENGAGE-AF-TIMI 48 (mean: 2.4 vs 1.6).
Our analyses on differences among geographical regions regarding patient characteristics and prescription patterns using baseline data from ETNA-AF-Europe show three important observations. First, the 30 mg dose of edoxaban was used much more frequently in OEC than in BeNe. Second, compared with those from OEC, patients from BeNe had slightly better overall prognostic characteristics. Lastly, patients from BeNe once enrolled in ENGAGE-AF-TIMI 48 generally had characteristics that put them at much higher baseline risks of stroke than those from our cohort.
Our results show that the 30 mg dose was used far less frequently in BeNe than in the OEC. However, rates of use of the 30 mg dose in the absence of any dose reduction criteria were similar in both regions, which can only be explained by relatively fewer patients in BeNe than in OEC with criteria for dose reduction: 14.5% in BeNe had a CrCl ≤50 ml/min compared with 22.4% in OEC; and 8.9% and 10.7% had a body weight ≤60 kg in BeNe and OEC, respectively. Often, such characteristics are related to other comorbidities, and consequently also to worse prognostic characteristics. That patients in BeNe, in fact, had better prognostic characteristics than those in OEC is evidenced by three observations.
First, a history of hypertension and diabetes mellitus was less common in BeNe, resulting in slightly lower mean CHA 2DS 2-VASc (−0.4) and HAS-BLED (−0.2) scores. Second, patients were less often considered frail in BeNe than in OEC (−5.8 percentage points). Lastly, more patients had paroxysmal AF in BeNe than in OEC (+14.0 percentage points), whereas permanent AF (−10.4 percentage points) was less often reported.
Aside from the role of chance, there are two potential explanations for the differences in clinical characteristics between BeNe and OEC: (a) other prescription preferences; and/or (b) other intrinsic risks.
It might be that physicians in BeNe prefer to prescribe edoxaban to AF patients with better risk profiles, and therefore the other NOACs to patients with worse profiles, and that this trend is less often observed in OEC (or perhaps not at all). For example, more patients in BeNe (3.8%) had a CHA 2DS 2-VASc of zero than in OEC (1.9%). This suggests that in our clinical practice edoxaban is more often prescribed for an upcoming or prior electrocardioversion or catheter ablation, and not for chronic stroke prevention, than in the other regions of Europe.
Whether this notion is correct, and whether there are truly other subgroups in which physicians from BeNe relative to those from other regions of Europe prefer to initiate edoxaban over the other NOACs (or vice versa) is still unknown. Some have addressed patterns of NOAC use in BeNe, but were unable to include data for edoxaban [ 18 ‐ 20 ]. Future studies that include all NOACs and address these issues are needed.
To our knowledge, no study has compared clinical characteristics of patients in either Belgium or the Netherlands prescribed one of the NOACs with those from OEC. Yet, when comparing the BeNe cohort with those used in other observational studies on NOACs, BeNe patients did not differ much with regard to age and CHA 2DS 2-VASc compared to those from Norway (mean age: 70.8–74.5 years; mean CHA 2DS 2-VASc: 2.5–2.9) [ 5 ], Scotland (mean age: 71.1–74.8 years; mean CHA 2DS 2-VASc: 2.5–3.0) [ 10 ], and the United Kingdom (mean age: 74.4–76.6 years; CHA 2DS 2-VASc: unknown) [ 14 ]. However, two studies on German and French patients with AF showed notably higher mean CHA 2DS 2-VASc scores compared with our cohort (3.7 vs 3.5–3.9 vs 2.8, respectively) [ 6, 8 ]. More studies on regional differences are needed to determine whether BeNe patients treated with oral anticoagulants are healthier than their peers from OEC.
Our comparisons illustrate that relative to Belgian and Dutch patients prescribed edoxaban in ETNA-AF-Europe, those from the corresponding countries in ENGAGE-AF-TIMI 48 had much higher mean CHA 2DS 2-VASc scores (+1.4), and much more often a history of any of the reported cardiovascular diseases (1.4- to 7.4-fold). Yet, our analyses also indicate that, compared with in the RCT, edoxaban is utilised in more patients with extreme characteristics in BeNe clinical practice, as demonstrated by more patients with a weight ≤60 kg (+5.3 percentage points), a CrCl ≤30 ml/min (+1.0 percentage point), and by overall higher HAS-BLED