Joint DOAC compared to VKA
The present study compares the relative risks of stroke, TIA, systemic embolism, and bleeding in patients with AF who have been prescribed either DOAC or VKA, based on a population of all residents in Germany with SHI in 2011–2016. After successful matching, the populations were considered as comparable regarding the included patient characteristics, whereby only confounders could be considered for which data were available (see the “Limitations” section). The findings show a generally increased risk of stroke and TIA as well as higher IR for mortality in DOAC users than in VKA users. The only Germany-related study, which jointly compared all DOAC users to VKA users, found similar effects for stroke, TIA, and mortality [16]. Deviating from Müller et al. [16], the present study revealed a generally lower risk of systemic embolism and bleeding in DOAC, compared to VKA users. For the endpoint systemic embolism, these differences might result from different inclusion criteria: In contrast to Müller et al. [16], the present study did not consider pulmonary embolisms in the analysis, as in patients with AF, DOACs are approved for prevention of stroke and systemic embolism but not for pulmonary embolism. Also, with regard to bleeding events, both studies differ. To capture all bleeding events which might be related to the pharmaceutical therapy, the present study comprehensively included non-traumatic bleeding events regardless of their location, while Müller et al. [16] included gastrointestinal bleedings and respiratory bleedings only. Nevertheless, similar directions for the relative risk of bleeding could have been expected. More similar to the present results, a meta-analysis of the pivotal studies of all DOACs showed lower risks of major bleeding in DOAC users compared to warfarin users [41]. In addition, two Germany-related studies that analyzed the risk of bleeding for each DOAC separately found lower risk of bleeding in apixaban and dabigatran users and a slightly increased [17] or similar [18] risk in rivaroxaban users, which also supports the present results.
Separate DOAC compared to VKA
Stroke, TIA, and systemic embolism
When analyzing the DOACs separately, an increased risk of stroke is found for dabigatran, rivaroxaban, and apixaban compared to VKAs. While Ujeyl et al. [18] also observed an increased risk of stroke for apixaban, the risk of stroke in dabigatran and rivaroxaban compared to VKA users was only non-significantly increased. This difference may be due to the lower statistical power of the previous study, as the present study analyzed 2–4 times the number of patients. In contrast, Hohenloser et al. [17] found a decreased risk of stroke in dabigatran and apixaban and no difference in rivaroxaban compared to VKA users. Similarly, also, the pivotal study of dabigatran found a decreased risk of stroke compared to warfarin [4], but all other DOACs showed no difference compared to warfarin [5,6,7]. The discrepancies between the pivotal studies and the present results may be caused by the different VKAs that have been used. While the TTR of patients treated with warfarin was 55–65% in the pivotal studies, the TTR in the German population (with 99% phenprocoumon prescriptions) can be assumed to be between 68 and 79% [14, 42]. A prolonged TTR can be expected to be associated with a reduced risk of stroke and as a consequence might result in a beneficial stroke prevention therapy compared to DOACs. Further, differences between the studies could stem from general methodological differences, such as inclusion criteria, which were broader in the present study. On the one hand, this procedure may allow less specific conclusions for individual subgroups of patients; on the other hand, the results may be more representative of the patients who actually receive OAC treatment. For instance, all pivotal studies excluded patients with an estimated creatinine clearance (CrCl) < 30 ml/min or < 25 ml/min (apixaban), while the present study does not differentiate between CrCl-levels. In patients with impaired renal function, considering an individual adjustment of the dose is recommended for all DOACs [38, 39, 43, 44]. While high concentrations of DOAC in serum increase the risk of bleeding [9], low doses increase the risk of stroke compared to high doses [4,5,6,7]. Especially for dabigatran, the uncertainty about an increased risk of bleeding shortly after approval [8], and particularly in patients with renal impairment [9], may have led to its cautious use, so that lower dosages rather than higher dosages tend to be prescribed. This approach could entail an increased risk of stroke, as found in the present study. A recent retrospective American study supports this explanatory approach: Shpak et al. [45] also found higher stroke incidences among overall DOAC compared to warfarin users. When considered individually, this effect was strongest for apixaban and dabigatran, whereas rivaroxaban showed only marginally and edoxaban no significantly increased stroke risk. In combination with reduced stroke and elevated intracranial bleeding risk in patients with strong anticoagulation, the authors see the results as an indication that DOAC patients may be less strongly anticoagulated than VKA patients. Because an easy-to-use test to evaluate the blood coagulability in DOAC users is lacking, and all DOAC have shorter half-lives than VKAs (5–17 h vs. 24–130 h), fluctuations in anticoagulation are more likely to occur with DOACs than with VKAs. Further investigations, in which patients with low and high DOAC doses are analyzed separately, are needed to reveal the reasons behind the increased risk of stroke in DOAC users. Unfortunately, the available data do not provide any information about clinical parameters that would indicate a justified dose reduction (such as CrCl or body weight). Furthermore, it is important to emphasize that the VKA and DOAC populations could only be adjusted as accurately as the available data allowed (see the “Limitations” section). Therefore, prospective studies are needed to further compare the effect of DOAC and VKA treatment in patients with impaired renal function.
Parallel to an increased stroke risk, DOAC users show the highest risk of a TIA when they received dabigatran, followed by apixaban and rivaroxaban. But the risk for systemic embolism is similar (dabigatran) or lower (rivaroxaban, apixaban, and edoxaban) in DOAC compared to VKA users. This is surprising as it may be assumed that the mechanisms behind strokes, TIA, and systemic embolisms caused by AF largely overlap. Thus, the same OAC should have similar effects on all these events. Notable, in the present study, the incidence of systemic embolism was much lower than the incidence of all other endpoints, leading to lower statistical power. As we still found a significant reduction in risk of embolism, the result may imply differences in the pathogenesis of strokes and systemic embolisms caused by AF.
Interestingly, edoxaban was the only DOAC to not show an increased but a similar risk of stroke and decreased risks of TIA and systemic embolism compared to VKAs. Similarly to apixaban and rivaroxaban, edoxaban acts by inhibiting the factor Xa and should therefore be expected to have comparable effects than other factor Xa inhibitors. In relation to edoxaban, but not apixaban and rivaroxaban, there have been concerns about low concentrations in serum, that is why the U.S. Food and Drug Administration (FDA) does not recommend edoxaban in AF patients with a CrCl > 95 ml/min [46]. High CrCl may lead to reduced efficacy of edoxaban. Even though in Germany no recommendations in relation to high CrCl levels have been published, the knowledge about the American conditions of use may have been influential. In case edoxaban is associated with rather low serum concentrations, higher doses may be more likely to be prescribed than lower doses. It is also conceivable that edoxaban is preferentially prescribed in patients with renal impairment, who can be assumed to have generally higher DOAC serum concentrations than patients without renal impairment. At least 20% of 70–79-year-old Germans has a renal impairment due to their age [47]. Both cases would lead to more efficient prevention of stroke, TIA, and embolism (as observed in the present study). However, the patient characteristics in the present study show that—with 13%— the percentage of patients with renal impairment is moderate and only the second highest in edoxaban users after apixaban user (15%), which partly contradicts the latter theory. Noteworthy, because in the present study, edoxaban is the latest DOAC approved in 2015, its users make up the smallest study population with the shortest follow-up period of max. 1 year. Therefore, the results should be interpreted with caution and future studies are necessary, to further investigate the observed differences between DOACs.
Bleeding and mortality
All DOACs but rivaroxaban showed a reduced risk of bleeding, which corresponds with the findings of Germany-related and international observational studies [11, 12, 17, 18, 48, 49]. Also, the pivotal studies of all DOAC showed lower (apixaban, edoxaban) or at least similar (dabigatran, rivaroxaban) risks of major bleeding in DOAC compared to warfarin users [4,5,6,7]. Edoxaban also showed a reduced risk of bleeding but was not yet analyzed by any Germany-related study or in comparison to the VKA phenprocoumon. The present bleeding-related results are in line with findings from the pivotal [5] and international studies [50].
Because the data provided no explicit information about mortality and similar criteria were used to determine therapy discontinuation and time of death (specific number of consecutive quarters without prescription/diagnosis), no statistical tests or HR but only IR are reported. The IR for mortality showed higher rates for dabigatran, rivaroxaban, and apixaban compared to VKA users, which is in line with higher IR for DOACs overall [16]. In contrast, Ujeyl et al. [18] and Hohnloser et al. [17] reported similar or lower IR for mortality in dabigatran users. Edoxaban showed lower IR for mortality while the pivotal study found no difference in risk [5]. The divergent findings underline the need to interpret the present results related to mortality with caution.
General
The results of the main analysis are supported by the sensitivity analyses, which indicate that the inclusion criteria were selected carefully and that all patients included in the analysis were AF patients who received OAC prescription for stroke prevention. Further, the inclusion of all doses in the analysis had no significant influence on the main results.
The therapy discontinuation in VKA users was much higher compared to DOAC users, which is well-known from previous international and Germany-related studies [16, 51, 52]. Similar to Müller et al. [16], in most cases, the therapy was discontinued early after only a few prescriptions, which explains the shorter mean follow-up time for VKA than for DOAC users. By censoring patients with therapy discontinuation, the present study accounted for this phenomenon.
Although the patient adherence could not be analyzed with the present data, it can be expected that the risk of an occurring event also depends on the regular intake of OACs. In line with the assumption that less frequently needed intake of tablets simplifies being adherent, several studies indicate that a once-daily treatment is associated with better treatment success than twice-daily treatment [53, 54]. In the present study, a similar pattern is observable, as dabigatran and apixaban user show a higher stroke risk compared to VKA user than rivaroxaban and edoxaban, which require a once-daily administration. On the contrary, there might be evidence that the risk of bleeding is lower in case of two-daily treatment because the dose is distributed throughout the day [54]. Taken together, the expected patient’s adherence should be considered in the decision for a specific OAC.
Limitations
The present study has several limitations. Importantly, the analyzed data are restricted to outpatient diagnoses and do not include any information from the inpatient sector. This means that patients, who are hospitalized after experiencing an event of interest, can only be observed at the time a doctor in the outpatient sector codes the relevant event. Therefore, the length of follow-up time may be prolonged after the event of interest actually occurred. As this applies to all patients independently of the OAC therapy, this should not bias the comparison between VKAs and DOACs. Further, patients who die in hospital after an event of interest can only be identified as deaths. Information on the diagnosis that led to hospitalization is missing, which results in an underestimation of the number of events actually occurring. Therefore, the absolute IR and HR numbers need to be treated with caution. However, since the relative number of events and most results are consistent with literature, the outpatient data should contain a reliable number of relevant diagnoses.
Also determined by the underlying data, the survival times were calculated based on quarters. Thus, an identification of survival time differences between patients with VKA and DOAC treatment is limited to a minimum of one quarter (see Table S1).
As in all studies that analyze observational data, the patient populations with DOAC and VKA treatment may still differ (marginally) in some of the considered characteristics despite the successful matching procedure. Further, limited adjustment was possible for characteristics such as alcohol consumption and smoking, which can be expected to be only diagnosed and coded in serious cases, while data of the regular consumption are missing. Similarly, no clinical measures were available to exactly adjust for hypertension (e.g., blood pressure), renal impairment (e.g., CrCl levels), and overweight (e.g., bodyweight). Also no socioeconomic data regarding income, education, and occupation group or data on ethnicity were available, which are known to influence the general health-related behavior [55]. However, the advantage of the present study is its large, representative dataset.