Background
Warfarin is commonly used as a secondary prevention of stroke in patients treated for Atrial Fibrillation (AF) [
1]. However, even if warfarin is used by majority of patients, it also has limitations. Recently, several new Direct Oral Anti-Coagulants (DOACs) have been approved for use by the Food and Drug Administrations [
2]. Even if these DOACs have previously been compared to warfarin [
3], they have seldom been compared with each other in systematic reviews. The indirect comparison of coronary risks associated with apixaban, rivaroxaban and dabigatran showed significant differences in safety outcomes with regards to acute coronary adverse events [
4]. Moreover, a network meta-analysis showed apixaban and 110 mg dabigatran twice a day to be more effective in patients with non-valvular AF whereas dabigatran 150 mg bid might be preferable compared to rivaroxaban, for patients with a high risk of embolism [
5]. However, direct head-to-head comparison of rivaroxaban and dabigatran has seldom been carried out. Therefore, this analysis aimed to compare the bleeding events associated with rivaroxaban and dabigatran in patients treated for AF.
Discussion
This analysis which aimed to compare (head to head) the bleeding outcomes associated with rivaroxaban versus dabigatran in patients treated for AF showed no significant difference in bleeding events, including intracranial and GI bleeding. Also, no significant difference was observed in stroke/SE/TIA and venous thromboembolism. However, mortality which was shown to favor dabigatran only approached significance.
Five observational studies were included in this current meta-analysis. The prospective cohort including patients with non-valvular AF recruited between February 2012 to August 2014 (with new users of 15 mg or 20 mg rivaroxaban respectively who were older and associated with more co-morbidities compared to new users with 110 or 150 mg dabigatran) showed rivaroxaban to be associated with a lower or similar proportion of stroke, but with an increased level of mortality and bleeding compared to dabigatran [
8]. Another prospective study used in this current analysis and including 69 patients showed adverse events with the use of rivaroxaban and dabigatran respectively due to their inappropriate use and suggested collaboration with clinical pharmacists for better use of these drugs [
9]. A French Nationwide Propensity-Matched Cohort Study which has been used in our current analysis showed similar bleeding and ischemic risks between rivaroxaban versus warfarin, and dabigatran and warfarin in the propensity-matched cohort [
10]. In addition, another study including 556 consecutive patients showed both drug rivaroxaban and dabigatran to be effective and safe compared to warfarin [
11]. Another head-to-head comparison on the other hand showed dabigatran and rivaroxaban to have a higher bleeding risk in the first 40 days, but dabigatran was not associated with an increased risk of GI bleeding [
12].
Previously, the indirect comparison involving 27 randomized trials showed significant differences in the comparative safety of apixaban, rivaroxaban and dabigatran [
4]. However, these DOACs were individually compared with warfarin whereby apixaban, rivaroxaban and dabigatran showed different results from this current analysis which compared rivaroxaban with dabigatran. Moreover, the network meta-analysis involving data from the RE-LY, ARISTOTLE and ROCKET AF trials, showed apixaban to be safer compared to rivaroxaban or dabigatran (150 mg) except that intracranial hemorrhage and all-cause mortality were similarly manifested [
5].
A study based in Australia showed both oral anticoagulants to be associated with considerable amount of hemorrhage within the first 30 days [
13]. Two hundred and forty hemorrhagic adverse events were observed with rivaroxaban whereas 504 events were observed among patients treated with dabigatran. But despite the fact that a higher rate of bleeding events was observed in both of the groups, rivaroxaban and dabigatran were barely compared.
Another study which included 444 patients with paroxysmal, persistent and longstanding-persistent AF showed comparable bleeding events between rivaroxaban and dabigatran [
14]. Even in the study published by Fontaine et al, a comparable major bleeding events was observed between these two DOACs [
15]. Similar to this current analysis, no significant difference in major complications was observed between these two DOACs. Also, a population based observational study showed a similar rate of GI bleeding associated with DOACs and warfarin [
16] but the authors emphasized on the fact that cautions should be taken when prescribing DOACs to older patients.
In a recently published meta-analysis showing the impact of DOACs on GI bleeding in patients with AF, the authors concluded that rivaroxaban, edoxaban and higher dosages of dabigatran should be avoided in patients who are at higher risk of suffering from GI bleeding [
17]. But the fact that their study only aimed to investigate GI bleeding associated with DOACs compared to warfarin should not be ignored and their conclusion was interpreted in comparison to warfarin whereas this current study compared rivaroxaban with dabigatran, instead of rivaroxaban with warfarin and dabigatran with warfarin respectively.
Coronary risk was also compared among the DOACs (dabigatran, apixaban and rivaroxaban), but even if a signal of increased coronary risk was observed with dabigatran, no direct comparison was made [
18] implying that head to head comparison was a major limitation in that study.
Another meta-analysis published by Caldeira et al showed that DOACs might be as safe as warfarin in patients who were to be treated for non-valvular AF [
19]. In addition, the study published by Yao et al, using patients from a large United States database, showed that in patients with non-valvular AF, dabigatran was associated with a similar rate of stroke, but with a lower rate of major bleeding when compared to warfarin [
20]. Also, when warfarin and rivaroxaban were compared, the latter was associated with similar rate of stroke and major bleeding. The network meta-analysis comparing the effectiveness of interventions for stroke prevention in patients with AF also showed all oral anticoagulants to reduce stroke/systemic embolism and mortality [
21].
Randomized trials have been conducted so far only to compare each of the DOACs with warfarin. However, no randomized trial has been conducted to show a head-to-head comparison between two different DOACs. There might be underlying market agreements aimed at avoiding conflicts of similar products, in view of the common goal, which is to subtract market space to Vitamin K antagonists.
DOACs might be cost-effective [
22] but their benefits should be further studied for future care. The Canada-based study comparing rivaroxaban with dabigatran in patients treated for AF found dabigatran to be economically dominant for the prevention of stroke and SE [
23]. The study by Miguel et al also showed dabigatran to improve clinical events with a lower cost, and it was preferred to rivaroxaban in Portuguese patients who suffered from AF [
24].
However, these hypotheses will have to be further proved in newer randomized trials beginning with the PREFER-AF trial which should be the first randomized trial evaluating vascular protective effects of these DOACs [
25]. The overall use of these DOACs will also depend on several factors such as patient satisfaction, cost, and risk profile of patients. Currently, it should not be ignored that the CHADS
2-VASC score is used to assess patients for the risk of stroke whereas the HAS-BLED score is used to calculate the risk of bleeding in patients who are treated by oral anticoagulants [
26,
27]. Renal function should also be taken into account before considering DOACs in patients with non-valvular AF [
28].
Novelty
The idea of this research is new in clinical medicine. Several DOACs have been approved for use in this new era. However, even if they have previously been compared with warfarin, they have seldom been directly compared with each other in systematic reviews and meta-analyses. By comparing rivaroxaban with dabigatran, this direct head to head analysis represents a new feature contributing to the literature of clinical medicine. Moreover, despite of including data obtained from observational studies, a very low level of heterogeneity was observed among all the subgroups analyzed which might be another new feature of this study.
Limitations
This study also has limitations. First of all, due to the restricted number of patients, this analysis might not provide robust results. In addition, only data from observational studies were included. Since data obtained from observational studies are not expected to be as good as data obtained from randomized trials, another limitation might be considered. Heterogeneous data which were included might also affect the results. Moreover, when analyzing stroke/SE/TIA, two studies which did not include TIA and SE respectively, were also included in this subgroup and analyzed due to a lack of data. This might also affect the result of this analysis. The follow-up periods reported in each study involved were also ignored, further contributing to the limitations in this study.
Acknowledgement
This research was supported by the Promotional Project of Guangxi Medical and Health Appropriate Technology (No. S201518).